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Non-pathogenic mismatch repair (MMR) gene variants can be associated with decreased MMR capacity in several settings. Due to an increased mutation rate, reduced MMR capacity leads to accumulation of somatic sequence changes in tumour suppressor genes such as in the neurofibromatosis type 1 (NF1) gene. Patients with autosomal dominant NF1 typically develop neurofibromas ranging from single to thousands. Concerning the number of neurofibromas NF1 patients face a situation that is still not predictable. A few studies suggested that germline non-pathogenic MMR gene variants modify the number of neurofibromas in NF1 and by this mechanism may promote the extent of neurofibroma manifestation. This review represents first evidence that specific non-pathogenic single nucleotide variants of MMR genes act as a modifier of neurofibroma manifestation in NF1, highlighting MSH2 re4987188 as the best analysed non-pathogenic variant so far. In summary, besides MSH2 promotor methylation, specific non-pathogenic germline MSH2 variants are associated with the extent of neurofibroma manifestation. Those variants can serve as a biomarker to facilitate better mentoring of NF1 patients at risk.
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Neurofibroma , Neurofibromatose 1 , Reparo de Erro de Pareamento de DNA/genética , Genes da Neurofibromatose 1 , Humanos , Neurofibroma/genética , Neurofibroma/patologia , Neurofibromatose 1/genéticaRESUMO
Neurofibromatosis type 1 (NF1) gene mutations or alterations occur within neurofibromatosis type 1 as well as in many different malignant tumours on the somatic level. In glioblastoma, NF1 loss of function plays a major role in inducing the mesenchymal (MES) subtype and, therefore defining the most aggressive glioblastoma. This is associated with an immune signature and mediated via the NF1-MAPK-FOSL1 axis. Specifically, increased invasion seems to be regulated via mutations in the leucine-rich domain (LRD) of the NF1 gene product neurofibromin. Novel targets for therapy may arise from neurofibromin deficiency-associated cellular mechanisms that are summarised in this review.
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Genes da Neurofibromatose 1 , Glioblastoma/genética , Mutação/genética , Neurofibromatose 1/genética , Animais , Humanos , Mesoderma/patologia , Modelos BiológicosRESUMO
BACKGROUND: Anticancer compound 3-bromopyruvate (3-BrPA) suppresses cancer cell growth via targeting glycolytic and mitochondrial metabolism. The malignant peripheral nerve sheath tumor (MPNST), a very aggressive, therapy resistant, and Neurofibromatosis type 1 associated neoplasia, shows a high metabolic activity and affected patients may therefore benefit from 3-BrPA treatment. To elucidate the specific mode of action, we used a controlled cell model overexpressing proteasome activator (PA) 28, subsequently leading to p53 inactivation and oncogenic transformation and therefore reproducing an important pathway in MPNST and overall tumor pathogenesis. METHODS: Viability of MPNST cell lines S462, NSF1, and T265 in response to increasing doses (0-120 µM) of 3-BrPA was analyzed by CellTiter-Blue® assay. Additionally, we investigated viability, reactive oxygen species (ROS) production (dihydroethidium assay), nicotinamide adenine dinucleotide dehydrogenase activity (NADH-TR assay) and lactate production (lactate assay) in mouse B8 fibroblasts overexpressing PA28 in response to 3-BrPA application. For all experiments normal and nutrient deficient conditions were tested. MPNST cell lines were furthermore characterized immunohistochemically for Ki67, p53, bcl2, bcl6, cyclin D1, and p21. RESULTS: MPNST significantly responded dose dependent to 3-BrPA application, whereby S462 cells were most responsive. Human control cells showed a reduced sensitivity. In PA28 overexpressing cancer cell model 3-BrPA application harmed mitochondrial NADH dehydrogenase activity mildly and significantly failed to inhibit lactate production. PA28 overexpression was associated with a functional glycolysis as well as a partial resistance to stress provoked by nutrient deprivation. 3-BrPA treatment was not associated with an increase of ROS. Starvation sensitized MPNST to treatment. CONCLUSIONS: Aggressive MPNST cells are sensitive to 3-BrPA therapy in-vitro with and without starvation. In a PA28 overexpression cancer cell model leading to p53 inactivation, thereby reflecting a key molecular feature in human NF1 associated MPNST, known functions of 3-BrPA to block mitochondrial activity and glycolysis were reproduced, however oncogenic cells displayed a partial resistance. To conclude, 3-BrPA was sufficient to reduce NF1 associated MPNST viability potentially due inhibition of glycolysis which should lead to the initiation of further studies and promises a potential benefit for NF1 patients.
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Inibidores Enzimáticos/uso terapêutico , Neurofibrossarcoma/tratamento farmacológico , Piruvatos/uso terapêutico , Proliferação de Células , Inibidores Enzimáticos/farmacologia , Humanos , Redes e Vias Metabólicas , Piruvatos/farmacologiaRESUMO
Individuals with cerebral palsy (CP) participate in reduced levels of physical activity and spend an increased amount of time in a sedentary state compared with healthy control subjects. Whether this in part can be explained by impaired muscle function is still unclear. The aim of the present study was to elucidate differences in muscle fibre recruitment during treadmill exercise between CP subjects and healthy age-, sex- and BMI-matched controls. This is a case-control study. Acoustic myography (AMG), a method recording fibre use and efficiency from contracting muscles, was applied during a period of treadmill exercise. The recorded AMG parameters revealed that the CP subjects had a significantly lower initial S-score (spatial summation) than the controls (P < 0.01). However, the T-score (temporal summation) and the E-score (efficiency) showed no significant differences between individuals with CP and the healthy control subjects. The present findings indicate that CP subjects use a higher degree of spatial summation (more fibres recruited) to keep up the same speed during treadmill exercise when compared to healthy matched control subjects. Our results suggest that individuals with CP have a tendency to recruit far more muscle fibres during bouts of exercise than healthy individuals. This may partly explain why CP subjects experience premature fatigue.
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Paralisia Cerebral/fisiopatologia , Exercício Físico , Músculo Esquelético/fisiopatologia , Miografia , Adulto , Feminino , Humanos , MasculinoRESUMO
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive neoplasms that commonly occur in patients with neurofibromatosis type 1 (NF1). Effective chemotherapy is not available. To characterize a therapeutic target for treatment, we investigated the role of cellular retinoic acid binding protein 2 (CRABP2) in MPNST in vitro. CRABP2 is a transcriptional co-activator of retinoic acid signaling. Although overexpression of CRABP2 is described in several cancers, it has not yet been studied in MPNSTs. We investigated CRABP2 expression in cultured Schwann cells and formalin-fixed, paraffin-embedded specimens of human peripheral nerve sheath tumors. A transient knockdown of CRABP2 was established in human NF1-associated MPNST cell lines (S462, T265, NSF1), and functional effects on viability, proliferation, apoptosis, and cytotoxicity were monitored. Finally, a 45-pathway reporter assay was performed in knockdown cells. Expression of CRABP2 was found in epithelium, fibroblasts, and tumor Schwann cells of skin, neurofibromas, and MPNSTs. In contrast, normal skin Schwann cells (NF1+/-, NF1-/-) did not express CRABP2. In the absence of retinoic acid, MPNST cells depleted of CRABP2 had reduced viability and proliferation, induction of apoptosis and cytotoxicity, and up-regulation of the type 1 interferon pathway. These data suggest a retinoic acid-independent, non-tumor suppressor role of CRABP2 for the survival of MPNST cells in vitro. Targeting CRABP2 overexpression may represent a unique approach for the treatment of human MPNSTs.
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Regulação Neoplásica da Expressão Gênica , Neoplasias de Bainha Neural/genética , Neurilemoma/genética , Neurofibroma/genética , Neurofibromatose 1/genética , Receptores do Ácido Retinoico/metabolismo , Apoptose , Carcinogênese , Proliferação de Células , Sobrevivência Celular , Expressão Gênica , Técnicas de Silenciamento de Genes , Genes Reporter , Humanos , Neoplasias de Bainha Neural/metabolismo , Neoplasias de Bainha Neural/patologia , Neurilemoma/metabolismo , Neurilemoma/patologia , Neurofibroma/metabolismo , Neurofibroma/patologia , Neurofibromatose 1/metabolismo , Neurofibromatose 1/patologia , Receptores do Ácido Retinoico/genética , Células de Schwann/metabolismo , Células de Schwann/patologia , Transdução de Sinais , Tretinoína/metabolismo , Regulação para CimaRESUMO
Neurofibromas and schwannomas are benign Schwann cell-derived peripheral nerve sheath tumors arising sporadically and within neurofibromatoses. Multiple tumors are a hallmark of neurofibromatosis type 1 (NF1) and type 2 (NF2) and schwannomatosis. Neurofibromas in NF1 and schwannomas in NF2 or schwannomatosis are defined by distinctive molecular hits. Among these, multiple hybrid neurofibromas/schwannomas may also appear, not yet being defined by a molecular background. We therefore performed molecular analysis of 22 hybrid neurofibromas/schwannomas using array comparative genomic hybridization, immunohistochemistry, quantitative RT-PCR, and functional analyses of cultured Schwann cells. Furthermore, we analyzed SMARCB1 by fluorescence in situ hybridization and multiplex ligation-dependent probe. Monosomy 22 was identified in 44% of tumors of tested patients with hybrid neurofibromas/schwannomas. In addition, in a single case, we detected focal deletion of the α-T-catenin/CTNNA3 gene (10q21.3). To further characterize this candidate, transient knockdown of α-T-catenin in Schwann cells was performed. CTNNA3 depleted cells showed cytoskeletal abnormalities and reduced E-cadherin expression, indicating epithelial-mesenchymal transition-like abnormalities. To conclude, we uncovered loss of chromosome 22 in almost half of all cases with hybrid neurofibromas/schwannomas of patients with multiple peripheral nerve sheath tumors. We tagged α-T-catenin/CTNNA3 as a novel candidate gene. Our functional investigations might indicate involvement of α-T-catenin/CTNNA3 in the biology of peripheral nerve sheath tumors.
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Neoplasias de Bainha Neural/genética , Neurilemoma/genética , Neurofibroma/genética , Neurofibromatoses/genética , Neurofibromatose 1/genética , Neoplasias Cutâneas/genética , alfa Catenina/genética , Adolescente , Adulto , Idoso , Cromossomos Humanos Par 22/genética , Hibridização Genômica Comparativa , Transição Epitelial-Mesenquimal , Feminino , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Monossomia , Neoplasias de Bainha Neural/patologia , Neurilemoma/patologia , Neurofibroma/patologia , Neurofibromatoses/patologia , Neurofibromatose 1/patologia , Células de Schwann/metabolismo , Células de Schwann/patologia , Neoplasias Cutâneas/patologia , Proteínas Supressoras de Tumor/genética , Adulto JovemRESUMO
BACKGROUND: Ganglioneuroma (GN) of the adult is a rare benign tumour originating from neural crest-derived cells. In most cases, GN is found in the mediastinum or retroperitoneum incidentally and may present with unspecific symptoms caused by space-occupying effects. The correct diagnosis of a retroperitoneal mass is still a challenge. Nevertheless, a preoperatively confirmed diagnosis of GN may support the concept of a less radical approach and may help to prevent unnecessary morbidity or loss of function. CASE PRESENTATION: We report a case of a symptomatic retroperitoneal paravertebral GN in a 33-year-old woman. She has been referred with abdominal discomfort, lancinating pain in the right leg, headache and nausea. Magnetic resonance imaging revealed a solid paravertebral tumour adjacent to the psoas muscle. Computed tomography-guided core needle biopsy yielded the diagnosis of GN. The tumour was resected completely via a laparotomy. Immunohistopathological examinations confirmed a benign GN. CONCLUSIONS: Diagnostic studies and therapeutic interventions of retroperitoneal GN are discussed. In our case, a core needle biopsy preceding complete resection was helpful to prevent too extensive surgical approach.
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Ganglioneuroma/diagnóstico , Ganglioneuroma/cirurgia , Microcirurgia , Neoplasias Retroperitoneais/diagnóstico , Neoplasias Retroperitoneais/cirurgia , Adulto , Biópsia com Agulha de Grande Calibre , Dor do Câncer/etiologia , Feminino , Ganglioneuroma/sangue , Ganglioneuroma/diagnóstico por imagem , Fogachos/etiologia , Humanos , Biópsia Guiada por Imagem , Laparotomia , Imageamento por Ressonância Magnética , Neoplasias Retroperitoneais/sangue , Neoplasias Retroperitoneais/diagnóstico por imagem , Espaço Retroperitoneal/patologia , Espaço Retroperitoneal/cirurgia , Tomografia Computadorizada por Raios X , Ultrassonografia , Conduta ExpectanteRESUMO
Gangliogliomas are well-differentiated, mixed glio-neuronal tumors of the CNS that are most frequently localized within the temporal lobe. In a minority of cases, gangliogliomas have been described in the brain stem where they may critically impinge anatomical structures. Rarely, ganglioglioma develop in cranial nerves, almost exclusively in the optic pathway, where they usually present as singular space-occupying masses. Here, we report on an 83-year-old patient who presented with unusual symmetrical, bilateral gangliogliomas of the trigeminal nerves. These tumors showed an exophytic growth within the subarachnoid space toward the Gasserian ganglion and surprisingly appeared as isointense masses on T1- and T2-weighted MRI. Due to their bilateral appearance, we performed array-comparative genomic hybridization (aCGH) on the gangliogliomas to address the possibility of an underlying tumor syndrome in this patient. To our knowledge, this is the first case of bilateral ganglioglioma of the trigeminal nerve described so far.
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Neoplasias dos Nervos Cranianos/patologia , Ganglioglioma/patologia , Doenças do Nervo Trigêmeo/patologia , Idoso de 80 Anos ou mais , Encéfalo/patologia , Neoplasias dos Nervos Cranianos/genética , Demência/etiologia , Ganglioglioma/genética , Humanos , Imuno-Histoquímica , Masculino , Nervo Trigêmeo/patologia , Doenças do Nervo Trigêmeo/genéticaRESUMO
Experimental animal studies of hypoxic-ischemic injury of the hippocampus of pigs are limited due to the unprecise definition of hippocampal subfields, cornu ammonis 1 to 4, compared to humans. Given that the pig model closely mirrors human physiology and serves as an important model for critical care research, a more precise description is necessary to draw valid conclusions applicable to human diseases. In our study, we were able to precisely define the CA2 and its adjacent regions in a domestic pig model by arginine vasopressin receptor 1B (AVPR1B) and calbindin-D28K like (CaBP-Li) expression patterns. Our findings demonstrate that the histoarchitecture of the porcine cornu ammonis subfields closely resembles that of the human hippocampus. Notably, we identified unusually strong neuronal damage in regions of the pig hippocampus following global ischemia, which are typically not susceptible to hypoxic-ischemic damage in humans.
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We describe the generation of two human induced pluripotent stem cell (iPSC) lines derived from peripheral blood mononuclear cells (PBMCs) using a non-integrative episomal reprogramming strategy. The first cell line was derived from a NF1 patient with the genetic variant c.1466A>G (BCRTi011-A) which leads to a cryptic splice site and aberrant splicing. The second one was created from a healthy relative of first-degree (BCRTi010-A). The generated iPSC lines were shown to have tri-lineage differentiation potential, a normal karyotype, and expression of pluripotent markers. Both iPSC lines provide a powerful tool for in vitro disease modeling and therapy development.
Assuntos
Células-Tronco Pluripotentes Induzidas , Neurofibromatose 1 , Humanos , Genes da Neurofibromatose 1 , Leucócitos Mononucleares , Neurofibromatose 1/genética , Diferenciação CelularRESUMO
Glioblastoma (GBM) is a highly aggressive brain tumor that often utilizes aerobic glycolysis for energy production (Warburg effect), resulting in increased methylglyoxal (MGO) production. MGO, a reactive dicarbonyl compound, causes protein alterations and cellular dysfunction via glycation. In this study, we investigated the effect of glycation on sialylation, a common post-translational modification implicated in cancer. Our experiments using glioma cell lines, human astrocytes (hA), and primary glioma samples revealed different gene expressions of sialyltransferases among cells, highlighting the complexity of the system. Glycation has a differential effect on sialyltransferase expression, upregulating ST8SIA4 in the LN229 and U251 cell lines and decreasing the expression in normal hA. Subsequently, polysialylation increased in the LN229 and U251 cell lines and decreased in hA. This increase in polysialylation could lead to a more aggressive phenotype due to its involvement in cancer hallmark processes such as immune evasion, resistance to apoptosis, and enhancing invasion. Our findings provide insights into the mechanisms underlying GBM aggressiveness and suggest that targeting glycation and sialylation could be a potential therapeutic strategy.
Assuntos
Glioblastoma , Glioma , Humanos , Glioblastoma/metabolismo , Óxido de Magnésio/uso terapêutico , Reação de Maillard , Linhagem Celular Tumoral , Glioma/metabolismo , Sialiltransferases/genéticaRESUMO
We report on a case of a fulminant non-aneurysmal subarachnoid hemorrhage after COVID-19 in a patient without previous medical history or known previous illness despite a COVID-19 infection one month prior. We saw rarefied vessels in the area of the left middle cerebral artery besides a massive left frontal hemorrhage on cranial imaging. We concluded that these rarefied vessels are the expression of an RCVS, which fits the history of progressive headaches for one month. The RCVS might be caused by the COVID-19 infection and is related to the hemorrhage. Unfortunately, due to preoperative entrapment, brain death occurred a few days later.
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BACKGROUND: Neurofibromatosis type 1 (NF1) is a frequent genetic disease characterized by multiple benign tumours with increased risk for malignancy. There is currently no biomarker for tumour load in NF1 patients. METHODS: In situ hybridization and quantitative real-time polymerase reaction were applied to investigate expression of cartilage-specific genes in mice bearing conditional inactivation of NF1 in the developing limbs. These mice do not develop tumours but recapitulate aspects of NF1 bone dysplasia, including deregulation of cartilage differentiation. It has been recently shown that NF1 tumours require for their growth the master regulator of cartilage differentiation SOX9. We thus hypothesized that some of the cartilage-specific genes deregulated in an Nf1Prx1 mouse model might prove to be relevant biomarkers of NF1 tumours. We tested this hypothesis by analyzing expression of the SOX9 target gene product melanoma-inhibitory activity/cd-rap (MIA) in tumour and serum samples of NF1 patients. RESULTS: Increased expression of Mia was found in Nf1-deficient cartilage in mice. In humans, MIA was expressed in all NF1-related tumours and its serum levels were significantly higher in NF1 patients than in healthy controls. Among NF1 patients, MIA serum levels were significantly higher in those with plexiform neurofibromas and in those with large number of cutaneous (> 1,000) or subcutaneous (> 100) neurofibromas than in patients without such tumours. Most notably, MIA serum levels correlated significantly with internal tumour burden. CONCLUSIONS: MIA is a potential serum biomarker of tumour load in NF1 patients which could be useful in following the disease course and monitoring the efficacy of therapies.
Assuntos
Biomarcadores Tumorais/análise , Proteínas da Matriz Extracelular/análise , Proteínas de Neoplasias/análise , Neurofibromatose 1/patologia , Carga Tumoral , Adolescente , Adulto , Idoso , Animais , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Adulto JovemRESUMO
MAP/ERK kinase 1 and 2 (MEK 1/2) inhibitors (MEKi) are investigated in several trials to treat lesions that arise from pathogenic variants of the Neurofibromatosis type 1 and type 2 genes (NF1, NF2). These trials showed that MEKi are capable to shrink volume of low grade gliomas and plexiform neurofibromas in NF1. Targeting other lesions being associated with a high morbidity in NF1 seems to be promising. Due to involvement of multiple pathways in NF2 associated lesions as well as in malignant tumors, MEKi are also used in combination therapies. This review outlines the current state of MEKi application in neurofibromatosis and associated benign and malignant lesions.
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Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder caused by heterozygotic inactivation of the NF1 tumor suppressor gene at 17q11.2. The associated phenotypes are highly variable, and modifying genes have been proposed to explain at least in part the intriguing expressivity. Given that haploinsufficiency of the NF1 gene product neurofibromin is responsible for some of the clinical manifestations, variations in expression of the wildtype NF1 allele might modify the phenotype. We therefore investigated epigenetic molecular modifications that could result in variable expression of the normal NF1 allele. To exclude confounding by DNA sequence variations, we analyzed monozygotic twin pairs with NF1 who presented with several discordant features. We fine-mapped the methylation pattern of a nearly 1 kb NF1 promoter region in lymphocytes of 8 twin pairs. All twin pairs showed significant intra-pair differences in methylation, especially of specific promoter subregions such as 5'UTR, exon 1 and intron 1 (+7 to +622), transcription factor binding sites and promoter elements like NF1HCS. Furthermore, we detected significant intra-pair differences in cytosine methylation for the region from -249 to -234 with regard to discordance for optic glioma with a higher grade of methylation in glioma cases. In conclusion, our findings of epigenetic differences of the NF1 promoter in leukocytes within mono zygotic twin pairs may serve as a proof of principle for other tissues. The results point towards a role of methylation patterns of the normal NF1 allele for expression differences and for modification of the NF1 phenotype.
Assuntos
Metilação de DNA , Doenças em Gêmeos/genética , Neurofibromatose 1/genética , Neurofibromina 1/genética , Gêmeos Monozigóticos/genética , Regiões não Traduzidas/genética , Adolescente , Adulto , Criança , Epigenômica , Éxons/genética , Feminino , Haploinsuficiência , Humanos , Íntrons/genética , Linfócitos/metabolismo , Linfócitos/patologia , Masculino , Glioma do Nervo Óptico/genética , Regiões Promotoras Genéticas/genéticaRESUMO
AIM: Prenatal and neonatal overfeeding programs a permanent obesity and diabetes disposition, e.g., due to induction of hypothalamic insulin resistance. We investigated acquired alterations of the DNA methylation pattern of the hypothalamic insulin receptor promoter (IRP) which might be an underlying molecular mechanism. METHODS: Neonatal overfeeding was induced by rearing Wistar rats in small litters (SL). Methylation of CpG-dinucleotides of the hypothalamic IRP was mapped using bisulfite sequencing. RESULTS: Neonatal overfeeding led to rapid early weight gain, resulting in a metabolic syndrome phenotype, i.e., obesity, hyperleptinemia, hyperglycemia, hyperinsulinemia, and increased insulin/glucose-ratio. The proportion of animals carrying any methylated CpG residue in the 322 bp CpG island of the IRP was increased in neonatally overfed SL rats (n=8), as compared to controls (n=8; P=0.04). Moreover, the mean percentage of methylated CpG positions was also higher in SL rats (P=0.01). Over both groups, neonatal blood glucose levels were positively correlated to the extent of promoter methylation (r=0.52; P=0.04). CONCLUSIONS: This study characterizes for the first time the IRP epigenomically in any species and tissue. Our data reveal that the IRP is vulnerable to hypermethylation due to overnutrition, probably especially glucose-dependent in a dose-response manner. This paradigmatically indicates the impact of nutrient-dependent epigenetic malprogramming, leading to a "diabesity" disposition which may become pathogenic throughout life.
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Epigênese Genética , Transtornos da Nutrição do Lactente/genética , Regiões Promotoras Genéticas , Receptor de Insulina/genética , Fenômenos Fisiológicos da Nutrição Animal , Animais , Animais Recém-Nascidos , Sequência de Bases , Glicemia/metabolismo , Ilhas de CpG , Metilação de DNA , Primers do DNA/genética , Feminino , Humanos , Hipotálamo/metabolismo , Transtornos da Nutrição do Lactente/sangue , Fenômenos Fisiológicos da Nutrição do Lactente , Recém-Nascido , Tamanho da Ninhada de Vivíparos , Masculino , Modelos Animais , Modelos Biológicos , Obesidade/etiologia , Obesidade/genética , Gravidez , Ratos , Ratos WistarRESUMO
Pre- and neonatal overfeeding programmes a permanent obesity disposition and accompanying diabetic and cardiovascular disorders, by unknown mechanisms. We proposed that early overfeeding may alter DNA methylation patterns of hypothalamic promoter regions of genes critically involved in the lifelong regulation of food intake and body weight. We induced neonatal overfeeding by rearing Wistar rats in small litters (SL) and thereafter mapped the DNA methylation status of CpG dinucleotides of gene promoters from hypothalamic tissue, using bisulfite sequencing. Neonatal overfeeding led to rapid early weight gain, resulting in a metabolic syndrome phenotype, i.e. obesity, hyperleptinaemia, hyperglycaemia, hyperinsulinaemia, and an increased insulin/glucose ratio. Accompanying, without group difference to controls, the promoter of the main orexigenic neurohormone, neuropeptide Y, was methylated at low levels (i.e. < 5%). In contrast, in SL rats the hypothalamic gene promoter of the main anorexigenic neurohormone, proopiomelanocortin (POMC), showed hypermethylation (P < 0.05) of CpG dinucleotides within the two Sp1-related binding sequences (Sp1, NF-kappaB) which are essential for the mediation of leptin and insulin effects on POMC expression. Consequently, POMC expression lacked upregulation, despite hyperleptinaemia and hyperinsulinaemia. Accordingly, the extent of DNA methylation within Sp1-related binding sequences was inversely correlated to the quotients of POMC expression/leptin (P = 0.02) and POMC expression/insulin (P < 0.001), indicating functionality of acquired epigenomic alterations. These data for the first time demonstrate a nutritionally acquired alteration of the methylation pattern and, consequently, the regulatory 'set point' of a gene promoter that is critical for body weight regulation. Our findings reveal overfeeding as an epigenetic risk factor of obesity programming and consecutive diabetic and cardiovascular disorders and diseases, in terms of the metabolic syndrome.
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Metilação de DNA , Epigênese Genética , Hiperfagia/genética , Doenças Metabólicas/genética , Obesidade/genética , Pró-Opiomelanocortina/genética , Regiões Promotoras Genéticas , Animais , DNA/genética , DNA/metabolismo , Regulação da Expressão Gênica , Humanos , Hiperfagia/metabolismo , Hipotálamo/fisiologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/fisiopatologia , Neuropeptídeo Y/genética , Neuropeptídeo Y/metabolismo , Obesidade/metabolismo , Obesidade/fisiopatologia , Pró-Opiomelanocortina/metabolismo , Ratos , Ratos WistarRESUMO
The etiology of primary brain tumors is largely unknown. Since a peak of incidence occurs during childhood, factors operating very early in life might play a key role. Previous studies have suggested that high birth weight is associated with an increased brain tumor risk. The authors conducted a meta-analysis on the association between birth weight and risk of specific histologic types of primary brain tumors. They included published studies (1966-2007) that reported odds ratios and 95% confidence intervals for brain tumors associated with birth weight. The authors identified eight studies involving 1,748,964 children, of whom 4,162 suffered from brain tumors of three histologic types (astrocytoma, medulloblastoma, and ependymoma). For astrocytoma, high birth weight (>4,000 g) was associated with increased risk (odds ratio = 1.38, 95% confidence interval (CI): 1.07, 1.79), with each 1,000-g increase in birth weight being associated with a 19% (95% CI: 4, 36) increase in risk. For medulloblastoma, high birth weight was also positively associated with increased risk (odds ratio = 1.27, 95% CI: 1.02, 1.60). No association was found for ependymoma. These findings indicate that birth weight is related to the development of childhood brain tumors, with high birth weight being a risk factor for the two most common types of brain tumors.
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Astrocitoma/epidemiologia , Peso ao Nascer , Neoplasias Encefálicas/epidemiologia , Ependimoma/epidemiologia , Macrossomia Fetal/epidemiologia , Meduloblastoma/epidemiologia , Astrocitoma/etiologia , Viés , Neoplasias Encefálicas/etiologia , Cocarcinogênese , Intervalos de Confiança , Fatores de Confusão Epidemiológicos , Modificador do Efeito Epidemiológico , Ependimoma/etiologia , Projetos de Pesquisa Epidemiológica , Macrossomia Fetal/etiologia , Humanos , Incidência , Recém-Nascido , Fator de Crescimento Insulin-Like I/fisiologia , Modelos Lineares , Meduloblastoma/etiologia , Dinâmica não Linear , Razão de Chances , Medição de Risco , Fatores de RiscoRESUMO
OBJECTIVE: To determine whether prenatal and perinatal maternal consumption of alcohol, tobacco and/or illicit drugs is associated with risk of neuroblastoma. DATA SOURCES: Medline and Embase (both from inception to February 2017), and reference lists of included studies. STUDY SELECTION: To be eligible, a study had to be an original report including data on intake of alcohol, tobacco smoking and/or consumption of illicit drugs during pregnancy and risk of neuroblastoma in the child. DATA EXTRACTION: From eligible studies, data study characteristics as well as effect measures and confounders were extracted. We assessed unadjusted and confounder-adjusted estimates, performed risk of bias analysis, constructed random-effects models and assessed heterogeneity. RESULTS: We identified 14 case-control studies (1987-2016) involving a total of 3114 children with neuroblastoma. Meta-analysis of unadjusted estimates showed an association between alcohol (OR 1.26; 95% CI 1.07 to 1.49), tobacco (OR 1.22; 95% CI 1.04 to 1.44) and illicit drug consumption during pregnancy and risk of neuroblastoma during childhood, with illicit drug consumption showing the strongest association (OR 3.26; 95% CI 1.36 to 7.86). However, adjusted estimates were highly heterogeneous. LIMITATIONS: All studies were at high risk of bias. CONCLUSIONS: Smoking, alcohol or illicit drugs during pregnancy might play a role in the development of neuroblastoma. However, well-designed studies are needed to assess whether these exposures are causal and whether time period during pregnancy, dose or co-consumption of substances is critical. TRIAL REGISTRATION NUMBER: Registration number CRD42016036165.
Assuntos
Neuroblastoma/epidemiologia , Complicações na Gravidez/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Transtornos Relacionados ao Uso de Substâncias , Feminino , Humanos , Gravidez , Fatores de Risco , Transtornos Relacionados ao Uso de Substâncias/classificação , Transtornos Relacionados ao Uso de Substâncias/epidemiologiaRESUMO
Muscle contractures are a common complication in patients with central nervous system (CNS) lesions which limit range of movement and cause joint deformities. Furthermore, it has previously been shown that muscles with contractures have a reduced number of capillaries, indicating decreased tissue vascularization. The aim of the present study was to investigate the microvascular volume (MV) at rest and after acute exercise in the muscle tissue of individuals with cerebral palsy (CP) and healthy control individuals. Contrast-enhanced ultrasound (CEUS) was used before and after 30 min of walking or running on a treadmill in 10 healthy control participants and 10 individuals with CP to detect MV of their skeletal muscle tissue. A significant increase in the MV was observed after exercise both in the adult CP group (21-53 yr) and in the control group (21-52 yr) (1.8 ± 0.8 ΔdB to 3.1 ± 0.9 ΔdB or 42.9% and 1.5 ± 0.6 ΔdB to 2.5 ± 0.9 ΔdB or 39.0%, respectively). Furthermore, a difference in the resting MV was observed between the most severe cases of CP [gross motor function classification scale (GMFCS) 3 and 4] (2.3 ± 0.5 ΔdB) and the less severe cases (GMFCS 1 and 2) (1.5 ± 0.2 ΔdB). When the CP group was walking (3.4 km/h), the lactate levels, Borg score, and heart rate matched the level of controls when they were running (9.8 km/h). In conclusion, individuals with CP become exhausted at much lower exercise intensities than healthy individuals. This is not explained by impaired microvascularization, since the MV of the individuals with CP respond normally to increased O2 demand during acute exercise. NEW & NOTEWORTHY Cerebral palsy (CP) patients were less physically active compared with typically developed individuals. This may affect the microvascularization. We observed that the CP group became exhausted at much lower exercise intensities compared with healthy individuals. However, impaired microvascularization was not the reason for the decreased physical activity as the CP group responded normally to increased O2 demand during acute exercise. These results indicate that walking may be recommended as an intervention to train and maintain skeletal muscle tissue in individuals with CP.