Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 164
Filtrar
Mais filtros

Base de dados
País/Região como assunto
Tipo de documento
Intervalo de ano de publicação
1.
Cell ; 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38986619

RESUMO

Posterior fossa group A (PFA) ependymoma is a lethal brain cancer diagnosed in infants and young children. The lack of driver events in the PFA linear genome led us to search its 3D genome for characteristic features. Here, we reconstructed 3D genomes from diverse childhood tumor types and uncovered a global topology in PFA that is highly reminiscent of stem and progenitor cells in a variety of human tissues. A remarkable feature exclusively present in PFA are type B ultra long-range interactions in PFAs (TULIPs), regions separated by great distances along the linear genome that interact with each other in the 3D nuclear space with surprising strength. TULIPs occur in all PFA samples and recur at predictable genomic coordinates, and their formation is induced by expression of EZHIP. The universality of TULIPs across PFA samples suggests a conservation of molecular principles that could be exploited therapeutically.

2.
Genome Res ; 34(3): 426-440, 2024 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-38621828

RESUMO

Genome structural variations within species are rare. How selective constraints preserve gene order and chromosome structure is a central question in evolutionary biology that remains unsolved. Our sequencing of several genomes of the appendicularian tunicate Oikopleura dioica around the globe reveals extreme genome scrambling caused by thousands of chromosomal rearrangements, although showing no obvious morphological differences between these animals. The breakpoint accumulation rate is an order of magnitude higher than in ascidian tunicates, nematodes, Drosophila, or mammals. Chromosome arms and sex-specific regions appear to be the primary unit of macrosynteny conservation. At the microsyntenic level, scrambling did not preserve operon structures, suggesting an absence of selective pressure to maintain them. The uncoupling of the genome scrambling with morphological conservation in O. dioica suggests the presence of previously unnoticed cryptic species and provides a new biological system that challenges our previous vision of speciation in which similar animals always share similar genome structures.


Assuntos
Genoma , Urocordados , Animais , Urocordados/genética , Urocordados/classificação , Evolução Molecular , Feminino , Filogenia , Masculino , Sintenia
3.
Nature ; 572(7767): 67-73, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31043743

RESUMO

Study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of development. Here we use single-cell transcriptomics to study more than 60,000 cells from the developing mouse cerebellum and show that different molecular subgroups of childhood cerebellar tumours mirror the transcription of cells from distinct, temporally restricted cerebellar lineages. The Sonic Hedgehog medulloblastoma subgroup transcriptionally mirrors the granule cell hierarchy as expected, while group 3 medulloblastoma resembles Nestin+ stem cells, group 4 medulloblastoma resembles unipolar brush cells, and PFA/PFB ependymoma and cerebellar pilocytic astrocytoma resemble the prenatal gliogenic progenitor cells. Furthermore, single-cell transcriptomics of human childhood cerebellar tumours demonstrates that many bulk tumours contain a mixed population of cells with divergent differentiation. Our data highlight cerebellar tumours as a disorder of early brain development and provide a proximate explanation for the peak incidence of cerebellar tumours in early childhood.


Assuntos
Neoplasias Cerebelares/genética , Neoplasias Cerebelares/patologia , Evolução Molecular , Feto/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Regulação Neoplásica da Expressão Gênica , Transcrição Gênica , Animais , Neoplasias Cerebelares/classificação , Cerebelo/citologia , Cerebelo/embriologia , Cerebelo/metabolismo , Criança , Feminino , Feto/citologia , Glioma/classificação , Glioma/genética , Glioma/patologia , Humanos , Meduloblastoma/classificação , Meduloblastoma/genética , Meduloblastoma/patologia , Camundongos , Análise de Sequência de RNA , Análise de Célula Única , Fatores de Tempo , Transcriptoma/genética
4.
Glob Chang Biol ; 30(1): e17020, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37947122

RESUMO

Gelatinous zooplankton are increasingly recognized to play a key role in the ocean's biological carbon pump. Appendicularians, a class of pelagic tunicates, are among the most abundant gelatinous plankton in the ocean, but it is an open question how their contribution to carbon export might change in the future. Here, we conducted an experiment with large volume in situ mesocosms (~55-60 m3 and 21 m depth) to investigate how ocean acidification (OA) extreme events affect food web structure and carbon export in a natural plankton community, particularly focusing on the keystone species Oikopleura dioica, a globally abundant appendicularian. We found a profound influence of O. dioica on vertical carbon fluxes, particularly during a short but intense bloom period in the high CO2 treatment, during which carbon export was 42%-64% higher than under ambient conditions. This elevated flux was mostly driven by an almost twofold increase in O. dioica biomass under high CO2 . This rapid population increase was linked to enhanced fecundity (+20%) that likely resulted from physiological benefits of low pH conditions. The resulting competitive advantage of O. dioica resulted in enhanced grazing on phytoplankton and transfer of this consumed biomass into sinking particles. Using a simple carbon flux model for O. dioica, we estimate that high CO2 doubled the carbon flux of discarded mucous houses and fecal pellets, accounting for up to 39% of total carbon export from the ecosystem during the bloom. Considering the wide geographic distribution of O. dioica, our findings suggest that appendicularians may become an increasingly important vector of carbon export with ongoing OA.


Assuntos
Água do Mar , Urocordados , Animais , Água do Mar/química , Ecossistema , Dióxido de Carbono/química , Carbono , Concentração de Íons de Hidrogênio , Plâncton , Fitoplâncton , Urocordados/fisiologia , Oceanos e Mares
5.
Childs Nerv Syst ; 40(3): 673-684, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37812266

RESUMO

PURPOSE: Intraventricular hemorrhage (IVH) of prematurity can lead to hydrocephalus, sometimes necessitating permanent cerebrospinal fluid (CSF) diversion. We sought to characterize the relationship between head circumference (HC) and ventricular size in IVH over time to evaluate the clinical utility of serial HC measurements as a metric in determining the need for CSF diversion. METHODS: We included preterm infants with IVH born between January 2000 and May 2020. Three measures of ventricular size were obtained: ventricular index (VI), Evan's ratio (ER), and frontal occipital head ratio (FOHR). The Pearson correlations (r) between the initial (at birth) paired measurements of HC and ventricular size were reported. Multivariable longitudinal regression models were fit to examine the HC:ventricle size ratio, adjusting for the age of the infant, IVH grade (I/II vs. III/IV), need for CSF diversion, and sex. RESULTS: A total of 639 patients with an average gestational age of 27.5 weeks were included. IVH grade I/II and grade III/IV patients had a positive correlation between initial HC and VI (r = 0.47, p < 0.001 and r = 0.48, p < 0.001, respectively). In our longitudinal models, patients with a low-grade IVH (I/II) had an HC:VI ratio 0.52 higher than those with a high-grade IVH (p-value < 0.001). Patients with low-grade IVH had an HC:ER ratio 12.94 higher than those with high-grade IVH (p-value < 0.001). Patients with low-grade IVH had a HC:FOHR ratio 12.91 higher than those with high-grade IVH (p-value < 0.001). Infants who did not require CSF diversion had an HC:VI ratio 0.47 higher than those who eventually did (p < 0.001). Infants without CSF diversion had an HC:ER ratio 16.53 higher than those who received CSF diversion (p < 0.001). Infants without CSF diversion had an HC:FOHR ratio 15.45 higher than those who received CSF diversion (95% CI (11.34, 19.56), p < 0.001). CONCLUSIONS: There is a significant difference in the ratio of HC:VI, HC:ER, and HC:FOHR size between patients with high-grade IVH and low-grade IVH. Likewise, there is a significant difference in HC:VI, HC:ER, and HC:FOHR between those who did and did not have CSF diversion. The routine assessments of both head circumference and ventricle size by ultrasound are important clinical tools in infants with IVH of prematurity.


Assuntos
Hidrocefalia , Doenças do Prematuro , Lactente , Recém-Nascido , Humanos , Recém-Nascido Prematuro , Ventrículos Cerebrais/cirurgia , Hidrocefalia/cirurgia , Idade Gestacional , Doenças do Prematuro/cirurgia , Hemorragia Cerebral/cirurgia , Estudos Retrospectivos
6.
Am J Respir Cell Mol Biol ; 67(4): 459-470, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-35895592

RESUMO

CD55 or decay accelerating factor (DAF), a ubiquitously expressed glycosylphosphatidylinositol (GPI)-anchored protein, confers a protective threshold against complement dysregulation which is linked to the pathogenesis of idiopathic pulmonary fibrosis (IPF). Since lung fibrosis is associated with downregulation of DAF, we hypothesize that overexpression of DAF in fibrosed lungs will limit fibrotic injury by restraining complement dysregulation. Normal primary human alveolar type II epithelial cells (AECs) exposed to exogenous complement 3a or 5a, and primary AECs purified from IPF lungs demonstrated decreased membrane-bound DAF expression with concurrent increase in the endoplasmic reticulum (ER) stress protein, ATF6. Increased loss of extracellular cleaved DAF fragments was detected in normal human AECs exposed to complement 3a or 5a, and in lungs of IPF patients. C3a-induced ATF6 expression and DAF loss was inhibited using pertussis toxin (an enzymatic inactivator of G-protein coupled receptors), in murine AECs. Treatment with soluble DAF abrogated tunicamycin-induced C3a secretion and ER stress (ATF6 and BiP expression) and restored epithelial cadherin. Bleomycin-injured fibrotic mice subjected to lentiviral overexpression of DAF demonstrated diminished levels of local collagen deposition and complement activation. Further analyses showed diminished release of DAF fragments, as well as reduction in apoptosis (TUNEL and caspase 3/7 activity), and ER stress-related transcripts. Loss-of-function studies using Daf1 siRNA demonstrated worsened lung fibrosis detected by higher mRNA levels of Col1a1 and epithelial injury-related Muc1 and Snai1, with exacerbated local deposition of C5b-9. Our studies provide a rationale for rescuing fibrotic lungs via DAF induction that will restrain complement dysregulation and lung injury.


Assuntos
Fibrose Pulmonar Idiopática , Lesão Pulmonar , Animais , Bleomicina , Antígenos CD55/genética , Antígenos CD55/metabolismo , Caderinas , Caspase 3/metabolismo , Complemento C3a , Complexo de Ataque à Membrana do Sistema Complemento , Proteínas do Sistema Complemento , Fibrose , Glicosilfosfatidilinositóis , Proteínas de Choque Térmico , Humanos , Fibrose Pulmonar Idiopática/patologia , Lesão Pulmonar/induzido quimicamente , Camundongos , Toxina Pertussis , RNA Mensageiro , RNA Interferente Pequeno , Tunicamicina
7.
Radiology ; 304(2): 406-416, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35438562

RESUMO

Background Radiogenomics of pediatric medulloblastoma (MB) offers an opportunity for MB risk stratification, which may aid therapeutic decision making, family counseling, and selection of patient groups suitable for targeted genetic analysis. Purpose To develop machine learning strategies that identify the four clinically significant MB molecular subgroups. Materials and Methods In this retrospective study, consecutive pediatric patients with newly diagnosed MB at MRI at 12 international pediatric sites between July 1997 and May 2020 were identified. There were 1800 features extracted from T2- and contrast-enhanced T1-weighted preoperative MRI scans. A two-stage sequential classifier was designed-one that first identifies non-wingless (WNT) and non-sonic hedgehog (SHH) MB and then differentiates therapeutically relevant WNT from SHH. Further, a classifier that distinguishes high-risk group 3 from group 4 MB was developed. An independent, binary subgroup analysis was conducted to uncover radiomics features unique to infantile versus childhood SHH subgroups. The best-performing models from six candidate classifiers were selected, and performance was measured on holdout test sets. CIs were obtained by bootstrapping the test sets for 2000 random samples. Model accuracy score was compared with the no-information rate using the Wald test. Results The study cohort comprised 263 patients (mean age ± SD at diagnosis, 87 months ± 60; 166 boys). A two-stage classifier outperformed a single-stage multiclass classifier. The combined, sequential classifier achieved a microaveraged F1 score of 88% and a binary F1 score of 95% specifically for WNT. A group 3 versus group 4 classifier achieved an area under the receiver operating characteristic curve of 98%. Of the Image Biomarker Standardization Initiative features, texture and first-order intensity features were most contributory across the molecular subgroups. Conclusion An MRI-based machine learning decision path allowed identification of the four clinically relevant molecular pediatric medulloblastoma subgroups. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Chaudhary and Bapuraj in this issue.


Assuntos
Neoplasias Cerebelares , Meduloblastoma , Adolescente , Neoplasias Cerebelares/diagnóstico por imagem , Neoplasias Cerebelares/genética , Criança , Pré-Escolar , Feminino , Proteínas Hedgehog/genética , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Meduloblastoma/diagnóstico por imagem , Meduloblastoma/genética , Estudos Retrospectivos
8.
Pediatr Neurosurg ; 57(4): 295-300, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35512661

RESUMO

INTRODUCTION: Intraoperative neuromonitoring (IONM) is commonly used during surgery of the spine and spinal cord for early surveillance of iatrogenic injury to the central and peripheral nervous system. However, for infants and young children under 3 years of age, the use of IONM is challenging due to incomplete central and peripheral myelination. CASE PRESENTATION: We report a case of a T4-T6 dermal sinus tract (DST) that was resected on day of life 23, with the successful use of IONM. CONCLUSION: To our knowledge, this is the youngest reported case of the use of IONM in the surgical correction of a DST in a neonatal patient. This case demonstrates the potential efficacy of IONM in neonatal spine surgery and the techniques used to adapt the technology to an immature nervous system.


Assuntos
Fístula , Monitorização Neurofisiológica Intraoperatória , Espinha Bífida Oculta , Criança , Pré-Escolar , Potencial Evocado Motor/fisiologia , Humanos , Lactente , Recém-Nascido , Monitorização Neurofisiológica Intraoperatória/métodos , Procedimentos Neurocirúrgicos/métodos , Estudos Retrospectivos , Espinha Bífida Oculta/diagnóstico por imagem , Espinha Bífida Oculta/cirurgia , Coluna Vertebral
9.
J Craniofac Surg ; 33(5): 1327-1330, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34930880

RESUMO

ABSTRACT: Blood loss is a main cause of morbidity after craniofacial procedures. The purpose of this study is to identify the incidence and predictors for transfusion of blood products in the endoscopic assisted strip craniectomy population. Data was prospectively collected from a single-center multi-surgeon cohort of 78 consecutive patients who underwent endoscopic assisted strip craniectomy for craniosynostosis between July 2013 and December 2020. The authors reviewed patient and treatment characteristics and outcomes. Of the 78 patients, 26 patients were transfused yielding an overall rate of transfusion of 33%. The most common fused suture was sagittal (n = 42, 54%) followed by metopic (n = 15, 19%), multiple (n = 10, 13%), coronal (n = 7, 9%) and finally lambdoid (n = 4, 5%). On univariate analysis, patients' weight in the transfusion cohort were significantly lower than those who did not receive a transfusion (5.6 ± 1.1 versus 6.5 ± 1.1 kg, P = 0.0008). The transfusion group also had significantly lower preoperative hemoglobin compared to the non-transfusion group (10.6 versus 11.1, P = .049). Eleven percent patients admitted to step-down received a transfusion, whereas 39% of patients admitted to the pediatric intensive care unit received a transfusion ( P = 0.042). On multivariate analysis, only higher patient weight (operating room [OR] 0.305 [0.134, 0.693], P = 0.005) was protective against a transfusion, whereas colloid volume (OR 1.018 [1.003, 1.033], P = 0.019) predicted the need for a transfusion.Our results demonstrate that endoscopic craniosynostosis cases carry a moderate risk of transfusion. individuals with lower weight and those that receive colloid volume are also at elevated risk.


Assuntos
Craniossinostoses , Perda Sanguínea Cirúrgica , Transfusão de Sangue/métodos , Criança , Craniossinostoses/epidemiologia , Craniotomia/métodos , Endoscopia/métodos , Humanos , Lactente , Procedimentos Neurocirúrgicos , Estudos Retrospectivos , Resultado do Tratamento
10.
Int J Mol Sci ; 23(3)2022 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-35163831

RESUMO

Cisplatin can induce peripheral neuropathy, which is a common complication of anti-cancer treatment and negatively impacts cancer survivors during and after completion of treatment; therefore, the mechanisms by which cisplatin alters sensory neuronal function to elicit neuropathy are the subject of much investigation. Our previous work suggests that the DNA repair activity of APE1/Ref-1, the rate-limiting enzyme of the base excision repair (BER) pathway, is critical for neuroprotection against cisplatin. A specific role for 8-oxoguanine DNA glycosylase-1 (OGG1), the glycosylase that removes the most common oxidative DNA lesion, and putative coordination of OGG1 with APE1/Ref-1 in sensory neurons, has not been investigated. We investigated whether inhibiting OGG1 glycosylase activity with the small molecule inhibitor, TH5487, and/or APE1/Ref-1 endonuclease activity with APE Repair Inhibitor III would alter the neurotoxic effects of cisplatin in sensory neuronal cultures. Sensory neuron function was assessed by calcitonin gene-related peptide (CGRP) release, as a marker of sensitivity and by neurite outgrowth. Cisplatin altered neuropeptide release in an inverse U-shaped fashion, with low concentrations enhancing and higher concentrations diminishing CGRP release. Pretreatment with BER inhibitors exacerbated the functional effects of cisplatin and enhanced 8oxo-dG and adduct lesions in the presence of cisplatin. Our studies demonstrate that inhibition of OGG1 and APE1 endonuclease activity enhances oxidative DNA damage and exacerbates neurotoxicity, thus limiting oxidative DNA damage in sensory neurons that might alleviate cisplatin-induced neuropathy.


Assuntos
Benzimidazóis/farmacologia , Cisplatino/toxicidade , DNA Glicosilases/metabolismo , DNA Liase (Sítios Apurínicos ou Apirimidínicos)/metabolismo , Piperidinas/farmacologia , Células Receptoras Sensoriais/metabolismo , Ubiquitina-Proteína Ligases/farmacologia , 8-Hidroxi-2'-Desoxiguanosina/metabolismo , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Células Cultivadas , Regulação para Baixo , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Estresse Oxidativo , Cultura Primária de Células , Ratos , Células Receptoras Sensoriais/citologia , Células Receptoras Sensoriais/efeitos dos fármacos
11.
Molecules ; 26(20)2021 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-34684680

RESUMO

A series of fourteen 2-aryl-3-phenyl-2,3-dihydro-4H-pyrido[3,2-e][1,3]thiazin-4-ones was prepared at room temperature by T3P-mediated cyclization of N-phenyl-C-aryl imines with thionicotinic acid, two difficult substrates. The reactions were operationally simple, did not require specialized equipment or anhydrous solvents, could be performed as either two or three component reactions, and gave moderate-good yields as high as 63%. This provides ready access to N-phenyl compounds in this family, which have been generally difficult to prepare. As part of the study, the first crystal structure of neutral thionicotinic acid is also reported, and showed the molecule to be in the form of the thione tautomer. Additionally, the synthesized compounds were tested against T. brucei, the causative agent of Human African Sleeping Sickness. Screening at 50 µM concentration showed that five of the compounds strongly inhibited growth and killed parasites.


Assuntos
Tiazinas , Trypanosoma brucei brucei/efeitos dos fármacos , Anidridos/química , Animais , Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Organofosfonatos/química , Tiazinas/síntese química , Tiazinas/farmacologia
12.
Dev Biol ; 443(2): 117-126, 2018 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-30217597

RESUMO

The mechanisms driving innovations that distinguish large taxons are poorly known and essentially accessible via a candidate gene approach. A spectacular acquisition by tunicate larvaceans is the house, a complex extracellular filtration device. Its components are secreted by the oikoplastic epithelium which covers the animal trunk. Here we describe the development of this epithelium in larvae through the formation of specific cellular territories known to produce distinct sets of house proteins (Oikosins). It involves cell divisions and morphological differentiation but very limited cell migration. A diverse set of homeobox genes, most often duplicated in the genome, are transiently and site-specifically expressed in the trunk epithelium at early larval stages. Using RNA interference, we show that two prop duplicates are involved in the differentiation of a region on and around the dorsal midline, regulating morphology and the production of a specific oikosin. Our observations favor a scenario in which multiple homeobox genes and most likely other developmental transcription factors were recruited for this innovation. Their frequent duplications probably predated, but were not required for the emergence of the house.


Assuntos
Genes Homeobox/genética , Urocordados/genética , Urocordados/metabolismo , Animais , Evolução Biológica , Células Epiteliais/metabolismo , Epitélio/embriologia , Epitélio/crescimento & desenvolvimento , Evolução Molecular , Regulação da Expressão Gênica no Desenvolvimento/genética , Larva/crescimento & desenvolvimento , Interferência de RNA , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
13.
BMC Genomics ; 20(1): 908, 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31783727

RESUMO

BACKGROUND: In phylogenetically diverse organisms, the 5' ends of a subset of mRNAs are trans-spliced with a spliced leader (SL) RNA. The functions of SL trans-splicing, however, remain largely enigmatic. RESULTS: We quantified translation genome-wide in the marine chordate, Oikopleura dioica, under inhibition of mTOR, a central growth regulator. Translation of trans-spliced TOP mRNAs was suppressed, consistent with a role of the SL sequence in nutrient-dependent translational control of growth-related mRNAs. Under crowded, nutrient-limiting conditions, O. dioica continued to filter-feed, but arrested growth until favorable conditions returned. Upon release from unfavorable conditions, initial recovery was independent of nutrient-responsive, trans-spliced genes, suggesting animal density sensing as a first trigger for resumption of development. CONCLUSION: Our results are consistent with a proposed role of trans-splicing in the coordinated translational down-regulation of nutrient-responsive genes under growth-limiting conditions.


Assuntos
Regulação da Expressão Gênica , Biossíntese de Proteínas , RNA Mensageiro/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Trans-Splicing , Transcrição Gênica , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/crescimento & desenvolvimento , Feminino , Mamíferos/genética , Motivos de Nucleotídeos , Oócitos/metabolismo , RNA Mensageiro/química , Serina-Treonina Quinases TOR/antagonistas & inibidores , Urocordados/genética
14.
BMC Genomics ; 19(1): 164, 2018 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-29482522

RESUMO

BACKGROUND: Development is largely driven by transitions between transcriptional programs. The initiation of transcription at appropriate sites in the genome is a key component of this and yet few rules governing selection are known. Here, we used cap analysis of gene expression (CAGE) to generate bp-resolution maps of transcription start sites (TSSs) across the genome of Oikopleura dioica, a member of the closest living relatives to vertebrates. RESULTS: Our TSS maps revealed promoter features in common with vertebrates, as well as striking differences, and uncovered key roles for core promoter elements in the regulation of development. During spermatogenesis there is a genome-wide shift in mode of transcription initiation characterized by a novel core promoter element. This element was associated with > 70% of male-specific transcription, including the use of cryptic internal promoters within operons. In many cases this led to the exclusion of trans-splice sites, revealing a novel mechanism for regulating which mRNAs receive the spliced leader. Binding of the cell cycle regulator, E2F1, is enriched at the TSS of maternal genes in endocycling nurse nuclei. In addition, maternal promoters lack the TATA-like element found in zebrafish and have broad, rather than sharp, architectures with ordered nucleosomes. Promoters of ribosomal protein genes lack the highly conserved TCT initiator. We also report an association between DNA methylation on transcribed gene bodies and the TATA-box. CONCLUSIONS: Our results reveal that distinct functional promoter classes and overlapping promoter codes are present in protochordates like in vertebrates, but show extraordinary lineage-specific innovations. Furthermore, we uncover a genome-wide, developmental stage-specific shift in the mode of TSS selection. Our results provide a rich resource for the study of promoter structure and evolution in Metazoa.


Assuntos
Cordados/genética , Regulação da Expressão Gênica no Desenvolvimento , Sítio de Iniciação de Transcrição , Animais , Cordados/metabolismo , Metilação de DNA , Genoma , Nucleossomos/metabolismo , Regiões Promotoras Genéticas , Espermatogênese , TATA Box , Transcrição Gênica
15.
J Neurooncol ; 139(3): 523-539, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29796724

RESUMO

BACKGROUND: Although the majority of current medulloblastoma adjuvant therapy protocols treat patients with ≥ 1.5 cm2 residual tumor as high risk with increased craniospinal irradiation, the true prognostic significance of extent of resection (EOR) in medulloblastoma is unknown. OBJECTIVES: We sought to synthesize the body of literature on EOR and survival to determine if a definitive association exists. DATA SOURCES/ELIGIBILITY CRITERIA: A PubMed search was conducted for the terms "medulloblastoma" combined with "extent of resection," "overall survival," "progression free survival," "gross total resection," "near total resection," "partial resection," or "subtotal resection." Studies that performed a statistical analysis of EOR and survival were included. RESULTS: Sixteen articles including 1489 patients found a statistically significant association between EOR and survival, 20 articles including 2335 patients did not find a significant association between EOR and survival, and 14 articles including 2950 patients had mixed results. The three articles that accounted for molecular subgroup found varying associations between EOR and progression free survival, while no association was found between EOR and overall survival. LIMITATIONS: This review is limited by inconsistent definitions of EOR, the retrospective nature of the articles analyzed, and infrequent use of multivariate statistical analyses. CONCLUSIONS: The prognostic importance of EOR for medulloblastoma is unclear and warrants re-evaluation, particularly in the context of molecular subgrouping.


Assuntos
Neoplasias Cerebelares/cirurgia , Meduloblastoma/cirurgia , Neoplasias Cerebelares/diagnóstico , Humanos , Meduloblastoma/diagnóstico , Procedimentos Neurocirúrgicos/métodos , Prognóstico
16.
J Neurooncol ; 140(2): 261-268, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30120661

RESUMO

INTRODUCTION: Pleomorphic xanthoastrocytoma (PXA) is a rare Grade II and III glioma. Surgical resection is the mainstay of treatment, however, adjuvant therapy is sometimes necessary. Given the rarity of PXA, chemotherapeutic efficacy data is limited. The importance of the BRAF V600E mutation in the context of MAP kinase pathway inhibition is unknown. The purpose of this study was to perform an in vivo screen of a variety to agents to determine efficacy against both V600E mutant and non-mutant PXA. METHODS: The efficacy of bevacizumab, temozolomide, lomustine (CCNU), irinotecan (CPT 11), a tyrosine kinase inhibitor (sorafenib), a selective MEK1/2 inhibitor (cobimetinib), and a BRAF inhibitor (vemurafenib) were assessed in two subcutaneous xenografts: D645 PXA (V600E-mutant) and D2363 PXA (V600E-non-mutant) (n = 5-10 mice). Select agents were also assessed in an intracranial model of D2363 PXA (n = 6-9). Subcutaneous tumor growth and survival were the endpoints. RESULTS: Temozolomide, bevacizumab, CPT 11, and sorafenib significantly inhibited subcutaneous tumor growth in both V600E-mutant and V600E-non-mutant models (P < 0.05). MEK inhibition (cobimetinib) but not BRAF inhibition (vemurafenib) also inhibited tumor growth regardless of V600E mutation (P < 0.05). Temozolomide, CPT 11, and bevacizumab also prolonged survival in a V600E-non-mutant intracranial model (median overall survival (OS) 68.5, 62.5, and 42.5 days, respectively) in contrast to controls (31.5 days, P < 0.001). CONCLUSIONS: These findings suggest that when adjuvant treatment is clinically indicated for PXA, temozolomide, CPT 11, or bevacizumab may be considered. Additionally, a trial of a MEK inhibitor or tyrosine kinase inhibitor could be considered for PXA regardless of V600E mutation status.


Assuntos
Astrocitoma/tratamento farmacológico , Astrocitoma/genética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Animais , Antineoplásicos/farmacologia , Bevacizumab/farmacologia , Linhagem Celular Tumoral , Feminino , Irinotecano/farmacologia , MAP Quinase Quinase Quinases/antagonistas & inibidores , MAP Quinase Quinase Quinases/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Mutação , Transplante de Neoplasias , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Distribuição Aleatória , Temozolomida/farmacologia
17.
Clin Neuropathol ; 37(5): 221-227, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30079884

RESUMO

INTRODUCTION: Edema is a significant cause of neuromorbidity in children and adults with brain tumors. Agents used to control this effect, such as corticosteroids, have their own associated morbidities. Sulfonylurea receptor 1 (SUR1) is a transmembrane protein that regulates the activity of ion channels in neurons, glia, and endothelial cells. SUR1 expression is upregulated in neuroinflammatory conditions. Inhibition of SUR1 with glyburide decreases edema and neuroinflammation by countering cytotoxic edema and apoptosis in rodent models of subarachnoid hemorrhage, stroke, trauma, and cerebral metastases. However, the expression of SUR1 in human brain tumors has not been elucidated. The purpose of this study was to determine SUR1 expression and cellular colocalization in a variety of human brain tumor specimens. MATERIALS AND METHODS: Six glioblastoma, 12 cerebral metastases, 11 medulloblastoma, 9 supratentorial ependymoma, and 8 posterior fossa ependymoma specimens were analyzed using immunofluorescence. SUR1 expression and colocalization with blood vessels, neurons, and glial cells was analyzed and compared using ANOVA. RESULTS: SUR1 expression was found in all specimens examined as a percentage of the total tissue area (mean ± SD): glioblastoma 3.9 ± 4, cerebral metastases 4.1 ± 3.1, medulloblastoma 8.2 ± 7.2, supratentorial ependymoma 9.1 ± 7, and posterior fossa ependymoma 8.1 ± 5.9. SUR1 expression was greater in supratentorial ependymoma compared to glioblastoma and metastases (p < 0.05) and greater in medulloblastoma compared to glioblastoma (p < 0.05). SUR1 colocalized most reliably with the neuronal marker, NeuN, in glioblastoma, metastases, and posterior fossa ependymoma samples (p < 0.05). SUR1 colocalized most reliably with the endothelial cell marker, CD31, in medulloblastoma samples (p < 0.05). CONCLUSION: SUR1 is a putative therapeutic target to reduce neuroinflammation in adult and pediatric brain tumors. Inhibition of SUR1 may result in neuronal stabilization in glioblastoma, cerebral metastases, and posterior fossa ependymoma and reduced edema in medulloblastoma.
.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Receptores de Sulfonilureias/biossíntese , Receptores de Sulfonilureias/genética , Adulto , Edema Encefálico/etiologia , Edema Encefálico/patologia , Neoplasias Encefálicas/complicações , Criança , Células Endoteliais/metabolismo , Humanos , Inflamação/patologia , Metástase Neoplásica , Neuroglia/metabolismo , Neurônios/metabolismo , Receptores de Sulfonilureias/antagonistas & inibidores
18.
Childs Nerv Syst ; 34(3): 449-455, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29151166

RESUMO

PURPOSE: Diffuse intrinsic pontine glioma (DIPG) remains the main cause of death in children with brain tumors. Given the inefficacy of numerous peripherally delivered agents to treat DIPG, convection enhanced delivery (CED) of therapeutic agents is a promising treatment modality. The purpose of this study was to determine which MR imaging type provides the best discrimination of intratumoral heterogeneity to guide future stereotactic implantation of CED catheters into the most cellular tumor regions. METHODS: Patients ages 18 years or younger with a diagnosis of DIPG from 2000 to 2015 were included. Radiographic heterogeneity index (HI) of the tumor was calculated by measuring the standard deviation of signal intensity of the tumor (SDTumor) normalized to the genu of the corpus callosum (SDCorpus Callosum). Four MR image types (T2-weighted, contrast-enhanced T1-weighted, FLAIR, and ADC) were analyzed at several time points both before and after radiotherapy and chemotherapy. HI values across these MR image types were compared and correlated with patient survival. RESULTS: MR images from 18 patients with DIPG were evaluated. The mean survival ± standard deviation was 13.8 ± 13.7 months. T2-weighted images had the highest HI (mean ± SD, 5.1 ± 2.5) followed by contrast-enhanced T1-weighted images (3.7 ± 1.5), FLAIR images (3.0 ± 1.1), and ADC maps (1.6 ± 0.4). ANOVA demonstrated that HI values were significantly higher for T2-weighted images than FLAIR (p < 0.01) and ADC (p < 0.0001). Following radiotherapy, T2-weighted and contrast-enhanced T1-weighted image HI values increased, while FLAIR and ADC HI values decreased. Univariate and multivariate analyses did not reveal a relationship between HI values and patient survival (p > 0.05). CONCLUSIONS: For children with DIPG, T2-weighted MRI demonstrates the greatest signal intensity variance suggesting tumor heterogeneity. Within this heterogeneity, T2-weighted signal hypointensity is known to correlate with increased cellularity and thus may represent a putative target for CED catheter placement in future clinical trials.


Assuntos
Neoplasias do Tronco Encefálico/diagnóstico por imagem , Glioma/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética/normas , Adolescente , Neoplasias do Tronco Encefálico/mortalidade , Neoplasias do Tronco Encefálico/terapia , Criança , Pré-Escolar , Feminino , Glioma/mortalidade , Glioma/terapia , Humanos , Aumento da Imagem/métodos , Aumento da Imagem/normas , Imageamento por Ressonância Magnética/mortalidade , Masculino , Taxa de Sobrevida/tendências
19.
J Craniofac Surg ; 29(7): 1767-1771, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30059426

RESUMO

BACKGROUND: Premature fusion of the cranial sutures can lead to significant neurocognitive, developmental, and esthetic consequences, especially if not corrected within the first year of life. This study aimed to identify the drivers of delayed cranial vault reconstruction (CVR) and its impact on complication and 30-day readmission rates among craniosynostosis patients. METHODS: The medical records of all children who underwent CVR for craniosynostosis between 2005 and 2017 at an academic institution were retrospectively reviewed. A delay in operation was defined by surgery performed >12 months of age. Patient demographics, comorbidities, perioperative complication rates, and 30-day readmission rates were collected. RESULTS: A total of 96 patients underwent primary CVR, with 79 (82.3%) patients undergoing nondelayed surgery and 17 (17.7%) patients undergoing surgery >12 months of age. Children undergoing delayed surgery were significantly more likely to be non-White (P < 0.0001), have Medicaid insurance (P = 0.023), and have a non-English primary language (P < 0.005). There was increased incidence of developmental disability identified at first consult (no-delay: 3.9% vs delay: 41.2%, P < 0.0001) and increased intracranial pressure (no-delay: 6.3% vs delay: 29.4%, P < 0.005) among children undergoing delayed surgery. The delayed cohort had a significantly higher unplanned 30-day readmission rate (no-delay: 0.0% vs delay: 5.9%, P = 0.03). CONCLUSION: Our study suggests that craniosynostosis patients who are non-White, have a non-English primary language, and have Medicaid insurance are at risk for delayed primary surgery, which may lead to increased 30-day readmission. Interventions are necessary to reduce craniosynostosis patients' barriers to care to minimize the sequelae associated with delayed surgery.


Assuntos
Craniossinostoses/cirurgia , Deficiências do Desenvolvimento/epidemiologia , Readmissão do Paciente , Procedimentos de Cirurgia Plástica , Complicações Pós-Operatórias/etiologia , Tempo para o Tratamento , Pré-Escolar , Craniossinostoses/complicações , Feminino , Disparidades em Assistência à Saúde , Humanos , Incidência , Lactente , Hipertensão Intracraniana/etiologia , Idioma , Masculino , Grupos Raciais , Procedimentos de Cirurgia Plástica/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Crânio/cirurgia , Fatores Socioeconômicos
20.
J Neurooncol ; 132(1): 83-87, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27864705

RESUMO

Pediatric surgical trials are rare and the impact of such trials on the institutions in which they are conducted is unknown. The purpose of this study was to analyze the clinical and financial impact of The Re-MATCH trial, a Phase I clinical trial requiring the biopsy or resection of recurrent medulloblastoma or PNET for enrollment. Inpatient financial and clinical volume information was collected during the 3 years of trial enrollment and the years preceding and following it. The primary endpoints were the difference in direct contribution margin (DCM), or net gain, of study and non-study patients and the difference in surgical volume during the study and non-study periods. The trial enrolled 18 patients; 15 had surgery at the sponsor institution and three had surgery at their home institution, then transferred tumor material to the sponsor institution. There were no differences between the two groups for potentially confounding variables such as neurosurgical procedure work relative value units (P = 0.13) or insurance provider (P = 0.26). There was no difference between the inpatient DCM per case for the institution for non-study patients (mean ± SD, $9039 ± $28,549) and study patients ($14,332 ± $20,231) (P = 0.4819). During the non-study period, there were a mean of 2.78 ± 1.65 pediatric brain tumor resections per month compared to 3.34 ± 1.66 cases per month during the study period, a 17% increase. When the 15 study patients were excluded, there were 2.97 ± 1.64 cases per month, a 7% increase. However, this increase in total case volume including study and non-study patients was not significant (P = 0.121). Phase I investigator-initiated surgically-based clinical trials may increase institutional surgical volume without imposing a financial burden. Finances are unlikely to be a barrier for researchers negotiating for resources to conduct such trials.


Assuntos
Neoplasias Encefálicas/economia , Neoplasias Encefálicas/cirurgia , Ensaios Clínicos Fase I como Assunto/economia , Meduloblastoma/economia , Meduloblastoma/cirurgia , Tumores Neuroectodérmicos Primitivos/economia , Tumores Neuroectodérmicos Primitivos/cirurgia , Criança , Humanos , Procedimentos Neurocirúrgicos/economia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA