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1.
Acta Neuropathol ; 146(4): 551-564, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37656187

RESUMO

Pilocytic astrocytoma (PA), the most common pediatric brain tumor, is driven by aberrant mitogen-activated protein kinase signaling most commonly caused by BRAF gene fusions or activating mutations. While 5-year overall survival rates exceed 95%, tumor recurrence or progression constitutes a major clinical challenge in incompletely resected tumors. Here, we used similarity network fusion (SNF) analysis in an integrative multi-omics approach employing RNA transcriptomic and mass spectrometry-based proteomic profiling to molecularly characterize PA tissue samples from 62 patients. Thereby, we uncovered that PAs segregated into two molecularly distinct groups, namely, Group 1 and Group 2, which were validated in three non-overlapping cohorts. Patients with Group 1 tumors were significantly younger and showed worse progression-free survival compared to patients with group 2 tumors. Ingenuity pathways analysis (IPA) and gene set enrichment analysis (GSEA) revealed that Group 1 tumors were enriched for immune response pathways, such as interferon signaling, while Group 2 tumors showed enrichment for action potential and neurotransmitter signaling pathways. Analysis of immune cell-related gene signatures showed an enrichment of infiltrating T Cells in Group 1 versus Group 2 tumors. Taken together, integrative multi-omics of PA identified biologically distinct and prognostically relevant tumor groups that may improve risk stratification of this single pathway driven tumor type.


Assuntos
Astrocitoma , Neoplasias Encefálicas , Criança , Humanos , Multiômica , Proteômica , Astrocitoma/genética , Neoplasias Encefálicas/genética , Potenciais de Ação
4.
J Neural Transm (Vienna) ; 121(4): 379-83, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24272680

RESUMO

Patients with Parkinson's disease receive selective irreversible monoamine oxidase (MAO)-B inhibitors, but their effects on MAO-A activity are not known during long-term application. We determined MAO-A inhibition in plasma samples from patients with MAO-B inhibitor intake or without MAO-B inhibitor treatment and from healthy controls. We detected a 70 % reduction of MAO-A activity in patients with MAO-B inhibitor therapy in comparison to the other groups. Our results suggest that treatment with MAO-B inhibitor may also influence MAO-A activity in vivo, when administered daily.


Assuntos
Indanos/uso terapêutico , Inibidores da Monoaminoxidase/uso terapêutico , Monoaminoxidase/sangue , Doença de Parkinson/sangue , Doença de Parkinson/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Relação Dose-Resposta a Droga , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
5.
J Neural Transm (Vienna) ; 120(1): 131-9, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22833045

RESUMO

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common psychiatric disorders in children and adolescents, with up to 5 % affected worldwide. Twin and family studies on ADHD show its high familiality with heritability estimated around 70 %, but, to date, no specific polymorphism or gene was found to be specifically affected. Psychostimulants (amphetamine, methylphenidate) and non-psychostimulants (atomoxetine) are used successfully in ADHD therapy, but many of their mechanisms of action and their adverse effects are not yet fully understood. Therefore, both genetic findings and therapeutic interventions should be further investigated. One easy platform for such studies is in vitro analyses, which encompass neuronal cell culture studies, transfections of genetic constructs, binding and electrophysiology analyses. In this review, different methods will be referred in particular to ADHD findings, and new techniques will be mentioned for future studies of drug or genetic effects in vitro.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/genética , Estimulantes do Sistema Nervoso Central/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Animais , Células Cultivadas , Estimulantes do Sistema Nervoso Central/farmacologia , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Regulação da Expressão Gênica/genética , Humanos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Noretandrolona/metabolismo , Polimorfismo Genético/genética , Transfecção
6.
J Neural Transm (Vienna) ; 120(1): 113-20, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22782687

RESUMO

Although Alzheimer's dementia (AD) is not characterised any longer simply as the accumulation and deposition of amyloid beta (Aß) peptides and hyperphosphorylation of tau proteins within the brain, excessive Aß(42) deposition is still considered to play a major role in this illness. Aß are able to adopt many differently aggregate forms, including amyloid fibrils as well as nonfibrillar structures (soluble Aß(42) oligomers). It is not well-established that which Aß(42) state is most responsible for AD or why. We wanted to verify which effects Aß(42) oligomers and aggregated peptides have on gene expression, protein level and enzyme activity of insulin and amyloid precursor protein (APP) pathways in vitro. Human neuroblastoma cells (SH-SY5Y) were treated with varying concentrations of soluble and aggregated Aß(42). Treatment effects on ß-secretase (BACE), glycogen synthase kinase 3α (GSK3α), glycogen synthase kinase 3ß (GSK3ß), phosphatidylinositol-3 kinase (PI-3K), insulin-degrading enzyme (IDE), insulin-receptor substrate 1 (IRS1), insulin receptor (INSR) and monoamine oxidase B (MAO-B) were investigated via quantitative-PCR, western blot, ELISA and enzyme activity assay. We could find different effects of soluble and aggregated peptides especially on gene/protein expression of GSK3ß and INSR and on GSK3ß and MAO-B activity. Soluble peptides showed significant effects leading to increased gene expression and protein amount of GSK3ß and to decreased level of gene and protein expression of INSR. MAO-B activity was enhanced after treatment with aggregated peptides and strongly inhibited after soluble Aß(42) treatment. Our data might provide insights into selective effects of specific forms of Aß(42) aggregates in AD.


Assuntos
Peptídeos beta-Amiloides/farmacologia , Precursor de Proteína beta-Amiloide/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Insulina/metabolismo , Fragmentos de Peptídeos/farmacologia , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Quinase 3 da Glicogênio Sintase/genética , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Insulina/genética , Insulisina , Monoaminoxidase/genética , Monoaminoxidase/metabolismo , Neuroblastoma/patologia , Fosfatidilinositol 3-Quinases , RNA Mensageiro/metabolismo , Receptor de Insulina/genética , Receptor de Insulina/metabolismo
7.
J Immunother Cancer ; 11(1)2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36639156

RESUMO

BACKGROUND: While major advances have been made in improving the quality of life and survival of children with most forms of medulloblastoma (MB), those with MYC-driven tumors (Grp3-MB) still suffer significant morbidity and mortality. There is an urgent need to explore multimodal therapeutic regimens which are effective and safe for children. Large-scale studies have revealed abnormal cancer epigenomes caused by mutations and structural alterations of chromatin modifiers, aberrant DNA methylation, and histone modification signatures. Therefore, targeting epigenetic modifiers for cancer treatment has gained increasing interest, and inhibitors for various epigenetic modulators have been intensively studied in clinical trials. Here, we report a cross-entity, epigenetic drug screen to evaluate therapeutic vulnerabilities in MYC amplified MB, which sensitizes them to macrophage-mediated phagocytosis by targeting the CD47-signal regulatory protein α (SIRPα) innate checkpoint pathway. METHODS: We performed a primary screen including 78 epigenetic inhibitors and a secondary screen including 20 histone deacetylase inhibitors (HDACi) to compare response profiles in atypical teratoid/rhabdoid tumor (AT/RT, n=11), MB (n=14), and glioblastoma (n=14). This unbiased approach revealed the preferential activity of HDACi in MYC-driven MB. Importantly, the class I selective HDACi, CI-994, showed significant cell viability reduction mediated by induction of apoptosis in MYC-driven MB, with little-to-no activity in non-MYC-driven MB, AT/RT, and glioblastoma in vitro. We tested the combinatorial effect of targeting class I HDACs and the CD47-SIRPa phagocytosis checkpoint pathway using in vitro phagocytosis assays and in vivo orthotopic xenograft models. RESULTS: CI-994 displayed antitumoral effects at the primary site and the metastatic compartment in two orthotopic mouse models of MYC-driven MB. Furthermore, RNA sequencing revealed nuclear factor-kB (NF-κB) pathway induction as a response to CI-994 treatment, followed by transglutaminase 2 (TGM2) expression, which enhanced inflammatory cytokine secretion. We further show interferon-γ release and cell surface expression of engulfment ('eat-me') signals (such as calreticulin). Finally, combining CI-994 treatment with an anti-CD47 mAb targeting the CD47-SIRPα phagocytosis checkpoint enhanced in vitro phagocytosis and survival in tumor-bearing mice. CONCLUSION: Together, these findings suggest a dynamic relationship between MYC amplification and innate immune suppression in MYC amplified MB and support further investigation of phagocytosis modulation as a strategy to enhance cancer immunotherapy responses.


Assuntos
Neoplasias Cerebelares , Glioblastoma , Meduloblastoma , Humanos , Camundongos , Animais , Meduloblastoma/tratamento farmacológico , NF-kappa B/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Proteína 2 Glutamina gama-Glutamiltransferase , Qualidade de Vida , Fagocitose , Macrófagos , Inflamação/metabolismo
8.
Front Immunol ; 13: 947961, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36524111

RESUMO

With growing molecular evidence for correlations between spatial arrangement of blood vasculature and fundamental immunological functions, carried out in distinct compartments of the subdivided lymph node, there is an urgent need for three-dimensional models that can link these aspects. We reconstructed such models at a 1.84 µm resolution by the means of X-ray phase-contrast imaging with a 2D Talbot array in a short time without any staining. In addition reconstructions are verified in immunohistochemistry staining as well as in ultrastructural analyses. While conventional illustrations of mammalian lymph nodes depict the hilus as a definite point of blood and lymphatic vessel entry and exit, our method revealed that multiple branches enter and emerge from an area that extends up to one third of the organ's surface. This could be a prerequisite for the drastic and location-dependent remodeling of vascularization, which is necessary for lymph node expansion during inflammation. Contrary to corrosion cast studies we identified B-cell follicles exhibiting a two times denser capillary network than the deep cortical units of the T-cell zone. In addition to our observation of high endothelial venules spatially surrounding the follicles, this suggests a direct connection between morphology and B-cell homing. Our findings will deepen the understanding of functional lymph node composition and lymphocyte migration on a fundamental basis.


Assuntos
Linfonodos , Vasos Linfáticos , Camundongos , Animais , Raios X , Linfonodos/diagnóstico por imagem , Vênulas , Vasos Linfáticos/diagnóstico por imagem , Tomografia , Mamíferos
9.
Neuro Oncol ; 24(9): 1509-1523, 2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-35307743

RESUMO

BACKGROUND: Intratumoral heterogeneity is crucially involved in metastasis, resistance to therapy, and cancer relapse. Amplifications of the proto-oncogene MYC display notable heterogeneity at the single-cell level and are associated with a particularly dismal prognosis in high-risk medulloblastomas (MBs). The aim of this study was to establish the relevance of interclonal cross-talk between MYC-driven and non-MYC-driven MB cells. METHODS: We used fluorescence in situ hybridization, single-cell transcriptomics, and immunohistochemistry, in vitro isogenic cell models, non-targeted proteomics, mass spectrometry-based metabolite quantification, HUVECs tube formation assay, and orthotopic in vivo experiments to investigate interclonal cross-talk in MB. RESULTS: We found that the release of lactate dehydrogenase A (LDHA) from MYC-driven cells facilitates metastatic seeding and outgrowth, while secretion of dickkopf WNT signaling pathway inhibitor 3 from non-MYC-driven cells promotes tumor angiogenesis. This tumor-supporting interaction between both subclones was abrogated by targeting the secretome through pharmacological and genetic inhibition of LDHA, which significantly suppressed tumor cell migration. CONCLUSION: Our study reveals the functional relevance of clonal diversity and highlights the therapeutic potential of targeting the secretome to interrupt interclonal communication and progression in high-risk MB.


Assuntos
Neoplasias Cerebelares , Meduloblastoma , Neoplasias Cerebelares/patologia , Humanos , Hibridização in Situ Fluorescente , Meduloblastoma/patologia , Prognóstico , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo
10.
Cell Death Dis ; 13(9): 806, 2022 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-36127323

RESUMO

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant brain tumor in infants that is characterized by loss of nuclear expression of SMARCB1 or SMARCA4 proteins. Recent studies show that AT/RTs comprise three molecular subgroups, namely AT/RT-TYR, AT/RT-MYC and AT/RT-SHH. The subgroups show distinct expression patterns of genes involved in ciliogenesis, however, little is known about the functional roles of primary cilia in the biology of AT/RT. Here, we show that primary cilia are present across all AT/RT subgroups with specific enrichment in AT/RT-TYR patient samples. Furthermore, we demonstrate that primary ciliogenesis contributes to AT/RT biology in vitro and in vivo. Specifically, we observed a significant decrease in proliferation and clonogenicity following disruption of primary ciliogenesis in AT/RT cell line models. Additionally, apoptosis was significantly increased via the induction of STAT1 and DR5 signaling, as detected by proteogenomic profiling. In a Drosophila model of SMARCB1 deficiency, concomitant knockdown of several cilia-associated genes resulted in a substantial shift of the lethal phenotype with more than 20% of flies reaching adulthood. We also found significantly extended survival in an orthotopic xenograft mouse model of AT/RT upon disruption of primary ciliogenesis. Taken together, our findings indicate that primary ciliogenesis or its downstream signaling contributes to the aggressiveness of AT/RT and, therefore, may constitute a novel therapeutic target.


Assuntos
Neoplasias Encefálicas , Tumor Rabdoide , Teratoma , Animais , Neoplasias Encefálicas/genética , Cílios/metabolismo , DNA Helicases/metabolismo , Humanos , Camundongos , Proteínas Nucleares/metabolismo , Tumor Rabdoide/genética , Tumor Rabdoide/metabolismo , Tumor Rabdoide/patologia , Transdução de Sinais , Teratoma/genética , Teratoma/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/uso terapêutico
11.
Nat Commun ; 13(1): 4061, 2022 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-35831316

RESUMO

Most lncRNAs display species-specific expression patterns suggesting that animal models of cancer may only incompletely recapitulate the regulatory crosstalk between lncRNAs and oncogenic pathways in humans. Among these pathways, Sonic Hedgehog (SHH) signaling is aberrantly activated in several human cancer entities. We unravel that aberrant expression of the primate-specific lncRNA HedgeHog Interacting Protein-AntiSense 1 (HHIP-AS1) is a hallmark of SHH-driven tumors including medulloblastoma and atypical teratoid/rhabdoid tumors. HHIP-AS1 is actively transcribed from a bidirectional promoter shared with SHH regulator HHIP. Knockdown of HHIP-AS1 induces mitotic spindle deregulation impairing tumorigenicity in vitro and in vivo. Mechanistically, HHIP-AS1 binds directly to the mRNA of cytoplasmic dynein 1 intermediate chain 2 (DYNC1I2) and attenuates its degradation by hsa-miR-425-5p. We uncover that neither HHIP-AS1 nor the corresponding regulatory element in DYNC1I2 are evolutionary conserved in mice. Taken together, we discover an lncRNA-mediated mechanism that enables the pro-mitotic effects of SHH pathway activation in human tumors.


Assuntos
Neoplasias Cerebelares , Meduloblastoma , MicroRNAs , RNA Longo não Codificante , Animais , Proteínas de Transporte/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias Cerebelares/genética , Dineínas/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Humanos , Meduloblastoma/genética , Glicoproteínas de Membrana/metabolismo , Camundongos , MicroRNAs/genética , RNA Longo não Codificante/genética
12.
BMC Med Genet ; 12: 151, 2011 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-22107728

RESUMO

BACKGROUND: Insulin-degrading enzyme (IDE) is the ubiquitously expressed enzyme responsible for insulin and amyloid beta (Aß) degradation. IDE gene is located on chromosome region 10q23-q25 and exhibits a well-replicated peak of linkage with Type 2 diabetes mellitus (T2DM). Several genetic association studies examined IDE gene as a susceptibility gene for Alzheimer's disease (AD), however with controversial results. METHODS: We examined associations of three IDE polymorphisms (IDE2, rs4646953; IDE7, rs2251101 and IDE9, rs1887922) with AD, Aß42 plasma level and T2DM risk in the longitudinal Vienna Transdanube Aging (VITA) study cohort. RESULTS: The upstream polymorphism IDE2 was found to influence AD risk and to trigger the Aß42 plasma level, whereas the downstream polymorphism IDE7 modified the T2DM risk; no associations were found for the intronic variant IDE9. CONCLUSIONS: Based on our SNP and haplotype results, we delineate the model that IDE promoter and 3' untranslated region/downstream variation may have different effects on IDE expression, presumably a relevant endophenotype with disorder-specific effects on AD and T2DM susceptibility.


Assuntos
Insulisina/genética , Polimorfismo de Nucleotídeo Único , Regiões 3' não Traduzidas , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/sangue , Estudos de Coortes , Diabetes Mellitus Tipo 2/genética , Estudos de Associação Genética , Genótipo , Haplótipos , Humanos , Estudos Longitudinais , Fragmentos de Peptídeos/sangue , Regiões Promotoras Genéticas , Risco
13.
J Neural Transm (Vienna) ; 118(3): 371-9, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20556444

RESUMO

Both Alzheimer's disease (AD), the most common form of dementia, and type-2 diabetes mellitus (T2DM), a disease associated with metabolic syndrome (MetS), affect a great number of the world population and both have increased prevalence with age. Recently, many studies demonstrated that pre-diabetes, MetS, and T2DM are risk factors in the development of AD and have many common mechanisms. The main focus of studies is the insulin resistance outcome found both in MetS as well as in brains of AD subjects. However, oxidative stress (OS)-related mechanisms, which are well known to be involved in AD, including mitochondrial dysfunction, elevated iron concentration, reactive oxygen species (ROS), and stress-related enzyme or proteins (e.g. heme oxygenase-1, transferrin, etc.), have not been elucidated in MetS or T2DM brains although OS and iron are involved in the degeneration of the pancreatic islet ß cells. Therefore, this review sets to cover the current literature regarding OS and iron in MetS and T2DM and the similarities to mechanisms in AD both in human subjects as well as in animal models.


Assuntos
Doença de Alzheimer/metabolismo , Ferro/metabolismo , Síndrome Metabólica/metabolismo , Encéfalo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Heme Oxigenase-1/metabolismo , Humanos , Estresse Oxidativo/fisiologia , Espécies Reativas de Oxigênio/metabolismo
14.
Cell Tissue Bank ; 12(4): 289-97, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-20652834

RESUMO

Postmortem brain tissue has been reported to be suitable to delineate regional pattern of possible disturbances underlying epigenetic functionality. However, from many parameters that have been detected in postmortem brain regions it is noteworthy that an effect of postmortem interval (PMI), storage time and premortem parameters should not be underestimated. Our previous investigation revealed that tryptophan (TRP) levels in postmortem brain tissue is affected by PMI and storage time. Since, alteration in TRP levels are assumed to be due to protein degradation, we further investigated whether TRP correlates to variables such as RNA, proteins and DNA modulators. In addition, we aimed to elucidate whether established postmortem variables may influence epigenetic parameters. These were investigated in well characterized postmortem human brain tissue originating from the European Brain Bank consortium II (BNEII). We could confirm previous findings, in which some protein levels alter because of prolonged PMI. Similarly, we demonstrated an influence of increased storage period on TRP levels, which might indicate degradation of proteins. Still not all proteins degrade in a similar manner, therefore a specific analysis for the protein of interest would be recommended. We found that methyltransferase- and acetyltransferase-activities were relatively preserved with PMI and storage duration. In conclusion, preservation of acetyltransferase- and methyltransferase-activities provides possible evidence of stability for epigenetic studies using postmortem tissue.


Assuntos
Acetiltransferases/metabolismo , Epigênese Genética , Metiltransferases/metabolismo , Mudanças Depois da Morte , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA/metabolismo , Estatísticas não Paramétricas , Preservação de Tecido , Triptofano/metabolismo
15.
Cell Death Dis ; 12(10): 885, 2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34584066

RESUMO

Glioblastoma is the most common malignant primary brain tumor. To date, clinically relevant biomarkers are restricted to isocitrate dehydrogenase (IDH) gene 1 or 2 mutations and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Long non-coding RNAs (lncRNAs) have been shown to contribute to glioblastoma pathogenesis and could potentially serve as novel biomarkers. The clinical significance of HOXA Transcript Antisense RNA, Myeloid-Specific 1 (HOTAIRM1) was determined by analyzing HOTAIRM1 in multiple glioblastoma gene expression data sets for associations with prognosis, as well as, IDH mutation and MGMT promoter methylation status. Finally, the role of HOTAIRM1 in glioblastoma biology and radiotherapy resistance was characterized in vitro and in vivo. We identified HOTAIRM1 as a candidate lncRNA whose up-regulation is significantly associated with shorter survival of glioblastoma patients, independent from IDH mutation and MGMT promoter methylation. Glioblastoma cell line models uniformly showed reduced cell viability, decreased invasive growth and diminished colony formation capacity upon HOTAIRM1 down-regulation. Integrated proteogenomic analyses revealed impaired mitochondrial function and determination of reactive oxygen species (ROS) levels confirmed increased ROS levels upon HOTAIRM1 knock-down. HOTAIRM1 knock-down decreased expression of transglutaminase 2 (TGM2), a candidate protein implicated in mitochondrial function, and knock-down of TGM2 mimicked the phenotype of HOTAIRM1 down-regulation in glioblastoma cells. Moreover, HOTAIRM1 modulates radiosensitivity of glioblastoma cells both in vitro and in vivo. Our data support a role for HOTAIRM1 as a driver of biological aggressiveness, radioresistance and poor outcome in glioblastoma. Targeting HOTAIRM1 may be a promising new therapeutic approach.


Assuntos
Glioblastoma/genética , Glioblastoma/radioterapia , MicroRNAs/metabolismo , Tolerância a Radiação/genética , Animais , Carcinogênese/genética , Carcinogênese/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Células Clonais , Regulação para Baixo/genética , Regulação Neoplásica da Expressão Gênica , Glioblastoma/patologia , Humanos , Camundongos Nus , MicroRNAs/genética , Mitocôndrias/metabolismo , Invasividade Neoplásica , Fenótipo , Prognóstico , Proteína 2 Glutamina gama-Glutamiltransferase/metabolismo , Proteogenômica , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio/metabolismo
16.
J Alzheimers Dis ; 16(3): 627-34, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19276557

RESUMO

Alzheimer's disease (AD), the most common cause of dementia, is a progressive neurodegenerative disease. At present, diagnosis of AD is rather late in the disease. Therefore, we attempted to find peripheral biomarkers for the early diagnosis of AD. We investigated the profiles of 33 genes, previously found by our group to have altered expression in postmortem brains of AD. The gene profiles were studied via quantitative-real-time-reverse-transcription-polymerase-chain-reaction, in whole blood samples (collected with the PAXgene blood RNA system) isolated from a population clinically diagnosed with AD and healthy controls (1-year period/ up to 4 samples). Five genes showed significant correlation to the dementia score, Mini-Mental State Examination (MMSE). Focusing on the two genes with the smallest p-value, H3-histone and cannabinoid-receptor-2, notable increases in these genes were found in peripheral blood mRNA in subjects with lower MMSE scores. Seasonal variations in gene expression were not significant due to sample size, but did seem to vary due to time of sample withdrawal. In conclusion, gene expression profiling might be a promising method to investigating a large population with the aim of developing an early diagnosis of AD.


Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Biomarcadores , Perfilação da Expressão Gênica , Testes Genéticos , Diagnóstico Precoce , Histonas/genética , Humanos , Receptores de Canabinoides/genética , Estações do Ano
17.
J Psychiatr Res ; 43(3): 298-308, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18603262

RESUMO

OBJECTIVES: In ageing population, both Alzheimer's disease (AD) and depression are common. Significant depressive symptoms are often co-morbid with cognitive impairment and dementia. In this study, we attempted to find various factors and markers for both AD and depression in a longitudinal cohort, the Vienna-Transdanube-Aging (VITA)-study. METHODS: The VITA-Study consisted of 305 healthy subjects, 174 subjects with depression only, 55 subjects diagnosed with AD only and 72 subjects with depression as well as AD. Associations between AD and/or depression to gene polymorphisms APO E (epsilon4), choline acetyltransferase (ChAT) 4G to A, serotonin-transporter gene promoter-length, dopamine-D4-receptor, ciliary-neurotrophic-factor-null mutation and brain-derived neurotrophic factor (C270T) and to various known factors were analyzed. RESULTS: AD and depression were significant associated. Significant risk factors found for AD were low education, low folic acid and depressive-symptoms, while for depression were low education and higher nonsteroidal anti-inflammatory drugs (NSAID) consume. Moreover, the ChAT polymorphism associated significant to depression. Gender, education, and ChAT significantly associated with the combination AD and/or depression. CONCLUSION: Such studies must be conducted cautiously, as co-morbidities and gene-environmental-social influences may sway the results dramatically. We found in the VITA-study significant association between depression and AD and between ChAT polymorphism and depression.


Assuntos
Doença de Alzheimer/genética , Transtorno Depressivo/genética , Predisposição Genética para Doença/genética , Polimorfismo Genético , Idoso , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/fisiopatologia , Apolipoproteínas E/genética , Áustria/epidemiologia , Fator Neurotrófico Derivado do Encéfalo/genética , Colina O-Acetiltransferase/genética , Fator Neurotrófico Ciliar/genética , Comorbidade , Transtorno Depressivo/epidemiologia , Transtorno Depressivo/fisiopatologia , Escolaridade , Feminino , Ácido Fólico/sangue , Genótipo , Humanos , Modelos Logísticos , Estudos Longitudinais , Masculino , Receptores de Dopamina D4/genética , Fatores de Risco , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Fatores Sexuais
18.
Transl Psychiatry ; 8(1): 51, 2018 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-29491375

RESUMO

Methylphenidate (Ritalin) is the most commonly prescribed drug in the treatment of attention-deficit hyperactivity disorder. It is suggested that in vivo, methylphenidate treatment supports cortical maturation, however, the molecular and cellular mechanisms are not well understood. This study aimed to explore the potential effect of methylphenidate on cell proliferation and maturation in various cellular models, hypothesizing its interaction with the Wnt-signaling. The termination of cell proliferation concomitant to neuronal maturation following methylphenidate treatment was observed in all of the cell-models tested: murine neural stem-, rat PC12- and the human SH-SY5Y-cells. Inhibition of Wnt-signaling in SH-SY5Y cells with Dkk1 30 min before methylphenidate treatment suppressed neuronal differentiation but enhanced proliferation. The possible involvement of the dopamine-transporter in cell differentiation was discounted following the observation of opposing results after GBR-12909 treatment. Moreover, Wnt-activation via methylphenidate was confirmed in Wnt-luciferase-reporter assay. These findings reveal a new mechanism of action of methylphenidate that might explain long-term effects.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Metilfenidato/farmacologia , Neurônios/efeitos dos fármacos , Via de Sinalização Wnt/efeitos dos fármacos , Animais , Linhagem Celular Tumoral , Embrião de Mamíferos , Fibroblastos/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Camundongos , Células-Tronco Neurais , Piperazinas/farmacologia , Ratos , Trombospondinas/farmacologia
19.
Eur J Hum Genet ; 26(1): 137-142, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29230040

RESUMO

The sonic hedgehog (SHH) signaling pathway has been shown to play important roles in embryogenesis, cell proliferation as well as in cell differentiation. It is aberrantly activated in various common cancers in adults, but also in pediatric neoplasms, such as rhabdomyosarcoma (RMS) and atypical teratoid/rhabdoid tumors (AT/RTs). Dysregulation and germline mutation in PATCHED1 (PTCH1), a receptor for SHH, is responsible for the Gorlin Syndrome, a familial cancer predisposing syndrome including RMS. Here, we report a newborn diagnosed with congenital embryonal RMS. Whole-exome sequencing (WES) identified the presence of two heterozygous germline mutations in two target genes of the SHH signaling pathway. The PTCH1 mutation p.(Gly38Glu) is inherited from the mother, whereas the PTCH2 p.(His622Tyr) mutation is transmitted from the father. Quantitative RT-PCR expression analysis of GLI and SMO, key players of the SHH pathway, showed significantly increase in the tumor tissue of the patient and also enrichment in the germline sample in comparison to the parents indicating activation of the SHH pathway in the patient. These findings demonstrate that SHH pathway activity seems to play a role in eRMS as evidenced by high expression levels of GLI1 RNA transcripts. We speculate that PTCH2 modulates tumorigenesis linked to the PTCH1 mutation and is likely associated with the congenital onset of the RMS observed in our patient.


Assuntos
Mutação em Linhagem Germinativa , Receptor Patched-1/genética , Receptor Patched-2/genética , Rabdomiossarcoma Embrionário/genética , Humanos , Recém-Nascido , Masculino , Rabdomiossarcoma Embrionário/patologia
20.
Cancer Cell ; 34(3): 379-395.e7, 2018 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-30205043

RESUMO

The current consensus recognizes four main medulloblastoma subgroups (wingless, Sonic hedgehog, group 3 and group 4). While medulloblastoma subgroups have been characterized extensively at the (epi-)genomic and transcriptomic levels, the proteome and phosphoproteome landscape remain to be comprehensively elucidated. Using quantitative (phospho)-proteomics in primary human medulloblastomas, we unravel distinct posttranscriptional regulation leading to highly divergent oncogenic signaling and kinase activity profiles in groups 3 and 4 medulloblastomas. Specifically, proteomic and phosphoproteomic analyses identify aberrant ERBB4-SRC signaling in group 4. Hence, enforced expression of an activated SRC combined with p53 inactivation induces murine tumors that resemble group 4 medulloblastoma. Therefore, our integrative proteogenomics approach unveils an oncogenic pathway and potential therapeutic vulnerability in the most common medulloblastoma subgroup.


Assuntos
Neoplasias Cerebelares/patologia , Meduloblastoma/patologia , Receptor ErbB-4/metabolismo , Quinases da Família src/metabolismo , Adolescente , Animais , Carcinogênese/patologia , Linhagem Celular Tumoral , Neoplasias Cerebelares/genética , Cerebelo/patologia , Criança , Pré-Escolar , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Lactente , Masculino , Meduloblastoma/genética , Camundongos , Camundongos Transgênicos , Fosforilação , Proteoma/metabolismo , Proteômica/métodos , Transdução de Sinais , Quinases da Família src/genética
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