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1.
Cell ; 186(4): 764-785.e21, 2023 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-36803604

RESUMO

The choroid plexus (ChP) is the blood-cerebrospinal fluid (CSF) barrier and the primary source of CSF. Acquired hydrocephalus, caused by brain infection or hemorrhage, lacks drug treatments due to obscure pathobiology. Our integrated, multi-omic investigation of post-infectious hydrocephalus (PIH) and post-hemorrhagic hydrocephalus (PHH) models revealed that lipopolysaccharide and blood breakdown products trigger highly similar TLR4-dependent immune responses at the ChP-CSF interface. The resulting CSF "cytokine storm", elicited from peripherally derived and border-associated ChP macrophages, causes increased CSF production from ChP epithelial cells via phospho-activation of the TNF-receptor-associated kinase SPAK, which serves as a regulatory scaffold of a multi-ion transporter protein complex. Genetic or pharmacological immunomodulation prevents PIH and PHH by antagonizing SPAK-dependent CSF hypersecretion. These results reveal the ChP as a dynamic, cellularly heterogeneous tissue with highly regulated immune-secretory capacity, expand our understanding of ChP immune-epithelial cell cross talk, and reframe PIH and PHH as related neuroimmune disorders vulnerable to small molecule pharmacotherapy.


Assuntos
Plexo Corióideo , Hidrocefalia , Humanos , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Plexo Corióideo/metabolismo , Hidrocefalia/líquido cefalorraquidiano , Hidrocefalia/imunologia , Imunidade Inata , Síndrome da Liberação de Citocina/patologia
2.
Cell ; 167(6): 1481-1494.e18, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27912058

RESUMO

Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. We previously described abnormalities in the branched-chain amino acid (BCAA) catabolic pathway as a cause of ASD. Here, we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to atypical brain amino acid profile, abnormal mRNA translation, and severe neurological abnormalities. Furthermore, we identified several patients with autistic traits and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. Finally, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for the BCAA in human brain function.


Assuntos
Transtorno do Espectro Autista/genética , Barreira Hematoencefálica/fisiopatologia , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Mutação , Aminoácidos/administração & dosagem , Aminoácidos/metabolismo , Animais , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/patologia , Transtorno do Espectro Autista/fisiopatologia , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Feminino , Humanos , Lactente , Recém-Nascido , Transportador 1 de Aminoácidos Neutros Grandes/genética , Masculino , Camundongos , Camundongos Knockout , Linhagem , Biossíntese de Proteínas , Receptor TIE-2/genética
3.
Cell ; 157(3): 651-63, 2014 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-24766810

RESUMO

Neurodegenerative diseases can occur so early as to affect neurodevelopment. From a cohort of more than 2,000 consanguineous families with childhood neurological disease, we identified a founder mutation in four independent pedigrees in cleavage and polyadenylation factor I subunit 1 (CLP1). CLP1 is a multifunctional kinase implicated in tRNA, mRNA, and siRNA maturation. Kinase activity of the CLP1 mutant protein was defective, and the tRNA endonuclease complex (TSEN) was destabilized, resulting in impaired pre-tRNA cleavage. Germline clp1 null zebrafish showed cerebellar neurodegeneration that was rescued by wild-type, but not mutant, human CLP1 expression. Patient-derived induced neurons displayed both depletion of mature tRNAs and accumulation of unspliced pre-tRNAs. Transfection of partially processed tRNA fragments into patient cells exacerbated an oxidative stress-induced reduction in cell survival. Our data link tRNA maturation to neuronal development and neurodegeneration through defective CLP1 function in humans.


Assuntos
Cerebelo/crescimento & desenvolvimento , Cerebelo/patologia , Fator de Especificidade de Clivagem e Poliadenilação/metabolismo , Proteínas Nucleares/genética , Fosfotransferases/genética , Splicing de RNA , RNA de Transferência/genética , Fatores de Transcrição/genética , Proteínas de Peixe-Zebra/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Fator de Especificidade de Clivagem e Poliadenilação/genética , Feminino , Humanos , Masculino , Camundongos , Modelos Moleculares , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Proteínas Nucleares/metabolismo , Linhagem , Fosfotransferases/metabolismo , RNA de Transferência/metabolismo , Saccharomyces cerevisiae/metabolismo , Fatores de Transcrição/metabolismo , Peixe-Zebra , Proteínas de Peixe-Zebra/genética
4.
Proc Natl Acad Sci U S A ; 120(16): e2214997120, 2023 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-37043537

RESUMO

While somatic variants of TRAF7 (Tumor necrosis factor receptor-associated factor 7) underlie anterior skull-base meningiomas, here we report the inherited mutations of TRAF7 that cause congenital heart defects. We show that TRAF7 mutants operate in a dominant manner, inhibiting protein function via heterodimerization with wild-type protein. Further, the shared genetics of the two disparate pathologies can be traced to the common origin of forebrain meninges and cardiac outflow tract from the TRAF7-expressing neural crest. Somatic and inherited mutations disrupt TRAF7-IFT57 interactions leading to cilia degradation. TRAF7-mutant meningioma primary cultures lack cilia, and TRAF7 knockdown causes cardiac, craniofacial, and ciliary defects in Xenopus and zebrafish, suggesting a mechanistic convergence for TRAF7-driven meningiomas and developmental heart defects.


Assuntos
Cardiopatias Congênitas , Neoplasias Meníngeas , Meningioma , Animais , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Cardiopatias Congênitas/genética , Neoplasias Meníngeas/genética , Meningioma/genética , Meningioma/patologia , Mutação , Crânio/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Humanos , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral
5.
Proc Natl Acad Sci U S A ; 118(36)2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34426522

RESUMO

The construction of population-based variomes has contributed substantially to our understanding of the genetic basis of human inherited disease. Here, we investigated the genetic structure of Turkey from 3,362 unrelated subjects whose whole exomes (n = 2,589) or whole genomes (n = 773) were sequenced to generate a Turkish (TR) Variome that should serve to facilitate disease gene discovery in Turkey. Consistent with the history of present-day Turkey as a crossroads between Europe and Asia, we found extensive admixture between Balkan, Caucasus, Middle Eastern, and European populations with a closer genetic relationship of the TR population to Europeans than hitherto appreciated. We determined that 50% of TR individuals had high inbreeding coefficients (≥0.0156) with runs of homozygosity longer than 4 Mb being found exclusively in the TR population when compared to 1000 Genomes Project populations. We also found that 28% of exome and 49% of genome variants in the very rare range (allele frequency < 0.005) are unique to the modern TR population. We annotated these variants based on their functional consequences to establish a TR Variome containing alleles of potential medical relevance, a repository of homozygous loss-of-function variants and a TR reference panel for genotype imputation using high-quality haplotypes, to facilitate genome-wide association studies. In addition to providing information on the genetic structure of the modern TR population, these data provide an invaluable resource for future studies to identify variants that are associated with specific phenotypes as well as establishing the phenotypic consequences of mutations in specific genes.


Assuntos
Variação Genética/genética , Genoma Humano/genética , Alelos , Consanguinidade , Exoma , Frequência do Gene/genética , Deriva Genética , Genética Populacional/métodos , Estudo de Associação Genômica Ampla/métodos , Genótipo , Haplótipos/genética , Migração Humana/tendências , Humanos , Turquia/etnologia , Sequenciamento do Exoma/métodos
6.
Int Ophthalmol ; 44(1): 388, 2024 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-39313744

RESUMO

PURPOSE: To evaluate the effect of subtenon platelet-rich plasma (PRP) treatment in retinitis pigmentosa (RP) patients and to determine the factors affecting the response to treatment. METHODS: For this purpose, 85 eyes of 43 RP patients with visual acuity of 1 logMAR and above were included in the study and subtenon autologous PRP treatment was applied 3 times at two-week intervals. In addition to a full ophthalmological examination, functional tests such as visual acuity, visual field, central retinal sensitivity measurement, and electroretinography (ERG) and structural measurements including the thickness of the outer retinal layers, and the length of the ellipsoid zone in optic coherence tomography, and the dimensions of the hyperautofluorescent ring in fundus autofluorescence imaging (FAF) were performed on the patients before and one month after the treatment. RESULTS: A statistically significant improvement was achieved in the patient's visual acuity, visual field MD and PSD index, and dark-adapted 10.0 ERG response b wave amplitude. There was no significant change in average central retinal sensitivity, fixation stability, outer retinal layer thickness and ellipsoid zone length. No statistically significant change was detected in the diameter and area of the hyperautofluorescence ring measured by FAF. It was found that the age of the patients and the age of onset of the disease were parameters affecting the treatment response. CONCLUSION: With PRP treatment applied periodically in RP patients, it may be possible to improve visual function and stop the progression of the disease, which can be detected by structural evaluations.


Assuntos
Eletrorretinografia , Plasma Rico em Plaquetas , Retinose Pigmentar , Tomografia de Coerência Óptica , Acuidade Visual , Campos Visuais , Humanos , Retinose Pigmentar/terapia , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/fisiopatologia , Masculino , Feminino , Adulto , Eletrorretinografia/métodos , Tomografia de Coerência Óptica/métodos , Pessoa de Meia-Idade , Campos Visuais/fisiologia , Resultado do Tratamento , Angiofluoresceinografia/métodos , Adulto Jovem , Retina , Seguimentos , Adolescente , Idoso
7.
Ann Neurol ; 91(1): 145-149, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34709661

RESUMO

We evaluated whether genetically elevated low-density lipoprotein cholesterol (LDL-C) levels are associated with lower risk of intracranial aneurysms and subarachnoid hemorrhage (IA/SAH). We conducted a 2-sample Mendelian randomization (MR) study. Our primary analysis used the inverse-variance weighted method. In secondary analyses, we implemented the MR-PRESSO method, restricted our analysis to LDL-C-specific instruments, and performed multivariate MR. A 1-mmol/l increase in genetically instrumented LDL-C levels was associated with a 17% lower risk of IA/SAH (odds ratio = 0.83, 95% confidence interval = 0.73-0.94, p = 0.004). Results remained consistent in secondary and multivariate analyses (all p < 0.05). Our results provide evidence for an inverse causal relationship between LDL-C levels and risk of IA/SAH. ANN NEUROL 2022;91:145-149.


Assuntos
LDL-Colesterol/sangue , LDL-Colesterol/genética , Hemorragia Subaracnóidea/sangue , Hemorragia Subaracnóidea/genética , Humanos , Análise da Randomização Mendeliana , Polimorfismo de Nucleotídeo Único
8.
J Neurooncol ; 161(2): 297-308, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36418843

RESUMO

INTRODUCTION: Meningiomas are associated with several gonadal steroid hormone-related risk factors and demonstrate a predominance in females. These associations led to investigations of the role that hormones may have on meningioma growth and development. While it is now accepted that most meningiomas express progesterone and somatostatin receptors, the conclusion for other receptors has been less definitive. METHODS: We performed a review of what is known regarding the relationship between hormones and meningiomas in the published literature. Furthermore, we reviewed clinical trials related to hormonal agents in meningiomas using MEDLINE PubMed, Scopus, and the NIH clinical trials database. RESULTS: We identify that all steroid-hormone trials lacked receptor identification or positive receptor status in the majority of patients. In contrast, four out of five studies involving somatostatin analogs used positive receptor status as part of the inclusion criteria. CONCLUSIONS: Several clinical trials have recently been completed or are now underway using somatostatin analogs in combination with other therapies that appear promising, but a reevaluation of hormone-based monotherapy is warranted. Synthesizing this evidence, we clarify the remaining questions and present future directions for the study of the biological role and therapeutic potential of hormones in meningioma and discuss how the stratification of patients using features such as grade, receptor status, and somatic mutations, might be used for future trials to select patients most likely to benefit from specific therapies.


Assuntos
Neoplasias Meníngeas , Meningioma , Feminino , Humanos , Meningioma/tratamento farmacológico , Meningioma/genética , Neoplasias Meníngeas/tratamento farmacológico , Neoplasias Meníngeas/genética , Receptores de Progesterona , Receptores de Estrogênio , Progesterona , Somatostatina/uso terapêutico
9.
J Hum Genet ; 67(9): 553-556, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35338243

RESUMO

Heterozygous mutations in Bicaudal D2 Drosophila homolog 2 (BICD2) gene, encodes a vesicle transport protein involved in dynein-mediated movement along microtubules, are responsible for an exceedingly rare autosomal dominant spinal muscular atrophy type 2A which starts in the childhood and predominantly effects lower extremities. Recently, a more severe form, type 2B, has also been described. Here, we present a patient born to a consanguineous union and who suffered from intellectual disability, speech delay, epilepsy, happy facial expression, truncal obesity with tappering fingers, and joint hypermobility. Whole-exome sequencing analysis revealed a rare, homozygous missense mutation (c.731T>C; p.Leu244Pro) in BICD2 gene. This finding presents the first report in the literature for homozygous BICD2 mutations and its association with a Cohen-Like syndrome. Patients presenting with Cohen-Like phenotypes should be further interrogated for mutations in BICD2.


Assuntos
Deficiência Intelectual , Atrofia Muscular Espinal , Genes Dominantes , Humanos , Deficiência Intelectual/genética , Proteínas Associadas aos Microtúbulos/genética , Atrofia Muscular Espinal/genética , Mutação , Mutação de Sentido Incorreto
10.
J Neurooncol ; 156(2): 205-214, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34846640

RESUMO

INTRODUCTION: Meningiomas are generally considered "benign," however, these tumors can demonstrate variability in behavior and a surprising aggressiveness with elevated rates of recurrence. The advancement of next-generation molecular technologies have led to the understanding of the genomic and epigenomic landscape of meningiomas and more recent correlations with clinical characteristics and behavior. METHODS: Based on a thorough review of recent peer-reviewed publications (PubMed) and edited texts, we provide a molecular overview of meningiomas with a focus on relevant clinical implications. RESULTS: The identification of specific somatic driver mutations has led to the classification of several major genomic subgroups, which account for more than 80% of sporadic meningiomas, and can be distinguished using noninvasive clinical variables to help guide management decisions. Other somatic genomic modifications, including non-coding alterations and copy number variations, have also been correlated with tumor characteristics. Furthermore, epigenomic modifications in meningiomas have recently been described, with DNA methylation being the most widely studied and potentially most clinically relevant. Based on these molecular insights, several clinical trials are currently underway in an effort to establish effective medical therapeutic options for meningioma. CONCLUSION: As we enhance our multiomic understanding of meningiomas, our ability to care for patients with these tumors will continue to improve. Further biological insights will lead to additional progress in precision medicine for meningiomas.


Assuntos
Neoplasias Meníngeas , Meningioma , Variações do Número de Cópias de DNA , Genômica , Humanos , Neoplasias Meníngeas/diagnóstico , Neoplasias Meníngeas/genética , Neoplasias Meníngeas/terapia , Meningioma/diagnóstico , Meningioma/genética , Meningioma/terapia
12.
Stroke ; 52(2): 582-587, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33440997

RESUMO

BACKGROUND AND PURPOSE: Animal and observational studies indicate that smoking is a risk factor for aneurysm formation and rupture, leading to nontraumatic subarachnoid hemorrhage (SAH). However, a definitive causal relationship between smoking and the risk of SAH has not been established. Using Mendelian randomization (MR) analyses, we tested the hypothesis that smoking is causally linked to the risk of SAH. METHODS: We conducted a 1-sample MR study using data from the UK Biobank, a large cohort study that enrolled over 500 000 Britons aged 40 to 69 from 2006 to 2010. Participants of European descent were included. SAH cases were ascertained using a combination of self-reported, electronic medical record, and death registry data. As the instrument, we built a polygenic risk score using independent genetic variants known to associate (P<5×10-8) with smoking behavior. This polygenic risk score represents the genetic susceptibility to smoking initiation. The primary MR analysis utilized the ratio method. Secondary MR analyses included the inverse variance weighted and weighted median methods. RESULTS: A total of 408 609 study participants were evaluated (mean age, 57 [SD 8], female sex, 220 937 [54%]). Among these, 132 566 (32%) ever smoked regularly, and 904 (0.22%) had a SAH. Each additional SD of the smoking polygenic risk score was associated with 21% increased risk of smoking (odds ratio [OR], 1.21 [95% CI, 1.20-1.21]; P<0.001) and a 10% increased risk of SAH (OR, 1.10 [95% CI, 1.03-1.17]; P=0.006). In the primary MR analysis, genetic susceptibility to smoking was associated with a 63% increase in the risk of SAH (OR, 1.63 [95% CI, 1.15-2.31]; P=0.006). Secondary analyses using the inverse variance weighted method (OR, 1.57 [95% CI, 1.13-2.17]; P=0.007) and the weighted median method (OR, 1.74 [95% CI, 1.06-2.86]; P=0.03) yielded similar results. There was no significant pleiotropy (MR-Egger intercept P=0.39; MR Pleiotropy Residual Sum and Outlier global test P=0.69). CONCLUSIONS: These findings provide evidence for a causal link between smoking and the risk of SAH.


Assuntos
Fumar/epidemiologia , Fumar/genética , Hemorragia Subaracnóidea/epidemiologia , Adulto , Idoso , Bases de Dados Factuais , Registros Eletrônicos de Saúde , Feminino , Predisposição Genética para Doença , Variação Genética , Humanos , Aneurisma Intracraniano/complicações , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Herança Multifatorial , Razão de Chances , Medição de Risco , Autorrelato , Acidente Vascular Cerebral/etiologia , Resultado do Tratamento , Reino Unido/epidemiologia
13.
Br J Haematol ; 193(2): 375-379, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33481259

RESUMO

SLIT2 constitutes a known tumour suppressor gene, which has not yet been implicated in the pathogenesis of primary central nervous system lymphoma (PCNSL). Performing exome sequencing on paired blood and tumour DNA samples from six treatment-naïve PCNSL patients, we identified novel SLIT2 variants (p.N63S, p.T590M, p.T732S) that were associated with shorter progression-free survival in our cohort and shorter overall survival in a large validation cohort of lymphoid malignancies from the cBio Cancer Genomics Portal. WNT- and NF-κB-reporter luciferase assays suggest detected alterations are loss-of-function variants. Given the possible prognostic implications, the role of SLIT2 in PCNSL pathogenesis and progression warrants further investigation.


Assuntos
Neoplasias do Sistema Nervoso Central/genética , Sequenciamento do Exoma/métodos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Linfoma não Hodgkin/genética , Proteínas do Tecido Nervoso/genética , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/virologia , Estudos de Coortes , Feminino , Variação Estrutural do Genoma/genética , Genômica/métodos , Herpesvirus Humano 4/genética , Humanos , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/mortalidade , Masculino , NF-kappa B/genética , Prognóstico , Intervalo Livre de Progressão , Estudos Retrospectivos
14.
J Hum Genet ; 66(2): 215-218, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32764695

RESUMO

Intellectual disability (ID) is a genetic and clinically heterogeneous common disease and underlying molecular pathogenesis can frequently not be identified by whole-exome/genome testing. Here, we report four siblings born to a consanguineous union who presented with intellectual disability and discuss the METAP1 pathway as a novel etiology of ID. Genomic analyses demonstrated that patients harbor a novel homozygous nonsense mutation in the gene METAP1. METAP1 codes for methionine aminopeptidase 1 (MetAP1) which oversees the co-translational excision of the first methionine remnants in eukaryotes. The loss-of-function mutations to this gene may result in a defect in the translation of many essential proteins within a cell. Improper neuronal function resulting from this loss of essential proteins could lead to neurologic impairment and ID.


Assuntos
Aminopeptidases/genética , Genes Recessivos , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Mutação , Adolescente , Criança , Feminino , Humanos , Masculino , Linhagem , Irmãos , Sequenciamento do Exoma
15.
Ann Neurol ; 88(1): 56-66, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32277781

RESUMO

OBJECTIVE: Observational studies point to an inverse correlation between low-density lipoprotein (LDL) cholesterol levels and risk of intracerebral hemorrhage (ICH), but it remains unclear whether this association is causal. We tested the hypothesis that genetically elevated LDL is associated with reduced risk of ICH. METHODS: We constructed one polygenic risk score (PRS) per lipid trait (total cholesterol, LDL, high-density lipoprotein [HDL], and triglycerides) using independent genomewide significant single nucleotide polymorphisms (SNPs) for each trait. We used data from 316,428 individuals enrolled in the UK Biobank to estimate the effect of each PRS on its corresponding trait, and data from 1,286 ICH cases and 1,261 matched controls to estimate the effect of each PRS on ICH risk. We used these estimates to conduct Mendelian Randomization (MR) analyses. RESULTS: We identified 410, 339, 393, and 317 lipid-related SNPs for total cholesterol, LDL, HDL, and triglycerides, respectively. All four PRSs were strongly associated with their corresponding trait (all p < 1.00 × 10-100 ). While one SD increase in the PRSs for total cholesterol (odds ratio [OR] = 0.92; 95% confidence interval [CI] = 0.85-0.99; p = 0.03) and LDL cholesterol (OR = 0.88; 95% CI = 0.81-0.95; p = 0.002) were inversely associated with ICH risk, no significant associations were found for HDL and triglycerides (both p > 0.05). MR analyses indicated that 1mmol/L (38.67mg/dL) increase of genetically instrumented total and LDL cholesterol were associated with 23% (OR = 0.77; 95% CI = 0.65-0.98; p = 0.03) and 41% lower risks of ICH (OR = 0.59; 95% CI = 0.42-0.82; p = 0.002), respectively. INTERPRETATION: Genetically elevated LDL levels were associated with lower risk of ICH, providing support for a potential causal role of LDL cholesterol in ICH. ANN NEUROL 2020 ANN NEUROL 2020;88:56-66.


Assuntos
Hemorragia Cerebral/sangue , Hemorragia Cerebral/genética , LDL-Colesterol/sangue , Predisposição Genética para Doença , Idoso , Idoso de 80 Anos ou mais , HDL-Colesterol/sangue , HDL-Colesterol/genética , LDL-Colesterol/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Triglicerídeos/sangue , Triglicerídeos/genética
16.
J Neurooncol ; 154(2): 237-246, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34350560

RESUMO

PURPOSE: As sphenoid wing meningiomas (SWMs) are associated with varying degrees of bony involvement, we sought to understand potential relationships between genomic subgroup and this feature. METHODS: Patients treated at Yale-New Haven Hospital for SWM were reviewed. Genomic subgroup was determined via whole exome sequencing, while the extent of bony involvement was radiographically classified as no bone invasion (Type I), hyperostosis only (Type II), tumor invasion only (Type III), or both hyperostosis and tumor invasion (Type IV). Among additional clinical variables collected, a subset of tumors was identified as spheno-orbital meningiomas (SOMs). Machine-learning approaches were used to predict genomic subgroups based on pre-operative clinical features. RESULTS: Among 64 SWMs, 53% had Type-II, 9% had Type-III, and 14% had Type-IV bone involvement; nine SOMs were identified. Tumors with invasion (i.e., Type III or IV) were more likely to be WHO grade II (p: 0.028). Additionally, tumors with invasion were nearly 30 times more likely to harbor NF2 mutations (OR 27.6; p: 0.004), while hyperostosis only were over 4 times more likely to have a TRAF7 mutation (OR 4.5; p: 0.023). SOMs were a significant predictor of underlying TRAF7 mutation (OR 10.21; p: 0.004). CONCLUSIONS: SWMs with invasion into bone tend to be higher grade and are more likely to be NF2 mutated, while SOMs and those with hyperostosis are associated with TRAF7 variants. Pre-operative prediction of molecular subtypes based on radiographic bony characteristics may have significant biological and clinical implications based on known recurrence patterns associated with genomic drivers and grade.


Assuntos
Hiperostose , Neoplasias Meníngeas , Meningioma , Genômica , Humanos , Hiperostose/diagnóstico por imagem , Hiperostose/genética , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/genética , Meningioma/diagnóstico por imagem , Meningioma/genética , Resultado do Tratamento
17.
Eur Radiol ; 30(7): 4145, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32152743

RESUMO

The original version of this article, published on 05 February 2020, unfortunately contained a mistake.

18.
Eur Radiol ; 30(6): 3073-3082, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32025832

RESUMO

OBJECTIVES: To establish a quantitative MR model that uses clinically relevant features of tumor location and tumor volume to differentiate lower grade glioma (LRGG, grades II and III) and glioblastoma (GBM, grade IV). METHODS: We extracted tumor location and tumor volume (enhancing tumor, non-enhancing tumor, peritumor edema) features from 229 The Cancer Genome Atlas (TCGA)-LGG and TCGA-GBM cases. Through two sampling strategies, i.e., institution-based sampling and repeat random sampling (10 times, 70% training set vs 30% validation set), LASSO (least absolute shrinkage and selection operator) regression and nine-machine learning method-based models were established and evaluated. RESULTS: Principal component analysis of 229 TCGA-LGG and TCGA-GBM cases suggested that the LRGG and GBM cases could be differentiated by extracted features. For nine machine learning methods, stack modeling and support vector machine achieved the highest performance (institution-based sampling validation set, AUC > 0.900, classifier accuracy > 0.790; repeat random sampling, average validation set AUC > 0.930, classifier accuracy > 0.850). For the LASSO method, regression model based on tumor frontal lobe percentage and enhancing and non-enhancing tumor volume achieved the highest performance (institution-based sampling validation set, AUC 0.909, classifier accuracy 0.830). The formula for the best performance of the LASSO model was established. CONCLUSIONS: Computer-generated, clinically meaningful MRI features of tumor location and component volumes resulted in models with high performance (validation set AUC > 0.900, classifier accuracy > 0.790) to differentiate lower grade glioma and glioblastoma. KEY POINTS: • Lower grade glioma and glioblastoma have significant different location and component volume distributions. • We built machine learning prediction models that could help accurately differentiate lower grade gliomas and GBM cases. We introduced a fast evaluation model for possible clinical differentiation and further analysis.


Assuntos
Neoplasias Encefálicas/diagnóstico , Glioma/diagnóstico , Aprendizado de Máquina , Imageamento por Ressonância Magnética/métodos , Estadiamento de Neoplasias/métodos , Adulto , Diagnóstico Diferencial , Feminino , Glioblastoma/diagnóstico , Humanos , Masculino , Máquina de Vetores de Suporte , Carga Tumoral
19.
J Med Genet ; 56(5): 332-339, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30487245

RESUMO

BACKGROUND: Putative nucleotidyltransferase MAB21L1 is a member of an evolutionarily well-conserved family of the male abnormal 21 (MAB21)-like proteins. Little is known about the biochemical function of the protein; however, prior studies have shown essential roles for several aspects of embryonic development including the eye, midbrain, neural tube and reproductive organs. OBJECTIVE: A homozygous truncating variant in MAB21L1 has recently been described in a male affected by intellectual disability, scrotal agenesis, ophthalmological anomalies, cerebellar hypoplasia and facial dysmorphism. We employed a combination of exome sequencing and homozygosity mapping to identify the underlying genetic cause in subjects with similar phenotypic features descending from five unrelated consanguineous families. RESULTS: We identified four homozygous MAB21L1 loss of function variants (p.Glu281fs*20, p.Arg287Glufs*14 p.Tyr280* and p.Ser93Serfs*48) and one missense variant (p.Gln233Pro) in 10 affected individuals from 5 consanguineous families with a distinctive autosomal recessive neurodevelopmental syndrome. Cardinal features of this syndrome include a characteristic facial gestalt, corneal dystrophy, hairy nipples, underdeveloped labioscrotal folds and scrotum/scrotal agenesis as well as cerebellar hypoplasia with ataxia and variable microcephaly. CONCLUSION: This report defines an ultrarare but clinically recognisable Cerebello-Oculo-Facio-Genital syndrome associated with recessive MAB21L1 variants. Additionally, our findings further support the critical role of MAB21L1 in cerebellum, lens, genitalia and as craniofacial morphogenesis.


Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Proteínas de Homeodomínio/genética , Mutação com Perda de Função , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Criança , Pré-Escolar , Consanguinidade , Fácies , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Proteínas de Homeodomínio/química , Homozigoto , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Modelos Moleculares , Linhagem , Polimorfismo de Nucleotídeo Único , Conformação Proteica , Síndrome , Sequenciamento do Exoma
20.
Proc Natl Acad Sci U S A ; 114(21): 5503-5508, 2017 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-28500274

RESUMO

Cerebral cavernous malformations (CCMs) are common vascular anomalies that develop in the central nervous system and, more rarely, the retina. The lesions can cause headache, seizures, focal neurological deficits, and hemorrhagic stroke. Symptomatic lesions are treated according to their presentation; however, targeted pharmacological therapies that improve the outcome of CCM disease are currently lacking. We performed a high-throughput screen to identify Food and Drug Administration-approved drugs or other bioactive compounds that could effectively suppress hyperproliferation of mouse brain primary astrocytes deficient for CCM3. We demonstrate that fluvastatin, an inhibitor of 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase and the N-bisphosphonate zoledronic acid monohydrate, an inhibitor of protein prenylation, act synergistically to reverse outcomes of CCM3 loss in cultured mouse primary astrocytes and in Drosophila glial cells in vivo. Further, the two drugs effectively attenuate neural and vascular deficits in chronic and acute mouse models of CCM3 loss in vivo, significantly reducing lesion burden and extending longevity. Sustained inhibition of the mevalonate pathway represents a potential pharmacological treatment option and suggests advantages of combination therapy for CCM disease.


Assuntos
Difosfonatos/uso terapêutico , Ácidos Graxos Monoinsaturados/uso terapêutico , Hemangioma Cavernoso do Sistema Nervoso Central/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Imidazóis/uso terapêutico , Indóis/uso terapêutico , Animais , Astrócitos/efeitos dos fármacos , Difosfonatos/farmacologia , Drosophila , Avaliação Pré-Clínica de Medicamentos , Quimioterapia Combinada , Células Endoteliais/efeitos dos fármacos , Feminino , Fluvastatina , Ensaios de Triagem em Larga Escala , Imidazóis/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Gravidez , Prenilação de Proteína/efeitos dos fármacos , Ácido Zoledrônico
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