RESUMO
In cancer, recurrent somatic single-nucleotide variants-which are rare in most paediatric cancers-are confined largely to protein-coding genes1-3. Here we report highly recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas. These mutations were not present across other subgroups of medulloblastoma, and we identified these hotspot mutations in U1 snRNA in only <0.1% of 2,442 cancers, across 36 other tumour types. The mutations occur in 97% of adults (subtype SHHδ) and 25% of adolescents (subtype SHHα) with SHH medulloblastoma, but are largely absent from SHH medulloblastoma in infants. The U1 snRNA mutations occur in the 5' splice-site binding region, and snRNA-mutant tumours have significantly disrupted RNA splicing and an excess of 5' cryptic splicing events. Alternative splicing mediated by mutant U1 snRNA inactivates tumour-suppressor genes (PTCH1) and activates oncogenes (GLI2 and CCND2), and represents a target for therapy. These U1 snRNA mutations provide an example of highly recurrent and tissue-specific mutations of a non-protein-coding gene in cancer.
Assuntos
Neoplasias Cerebelares/genética , Proteínas Hedgehog/genética , Meduloblastoma/genética , RNA Nuclear Pequeno/genética , Adolescente , Adulto , Processamento Alternativo , Proteínas Hedgehog/metabolismo , Humanos , Mutação , Sítios de Splice de RNA , Splicing de RNARESUMO
BACKGROUND: Glioblastoma (GBM) is the most common primary brain tumor in adults. Despite extensive research and clinical trials, median survival post-treatment remains at 15 months. Thus, all opportunities to optimize current treatments and improve patient outcomes should be considered. A recent retrospective clinical study found that taking TMZ in the morning compared to the evening was associated with a 6-month increase in median survival in patients with MGMT-methylated GBM. Here, we hypothesized that TMZ efficacy depends on time-of-day and O6-Methylguanine-DNA Methyltransferase (MGMT) activity in murine and human models of GBM. METHODS AND RESULTS: In vitro recordings using real-time bioluminescence reporters revealed that GBM cells have intrinsic circadian rhythms in the expression of the core circadian clock genes Bmal1 and Per2, as well as in the DNA repair enzyme, MGMT. Independent measures of MGMT transcript levels and promoter methylation also showed daily rhythms intrinsic to GBM cells. These cells were more susceptible to TMZ when delivered at the daily peak of Bmal1 transcription. We found that in vivo morning administration of TMZ also decreased tumor size and increased body weight compared to evening drug delivery in mice bearing GBM xenografts. Finally, inhibition of MGMT activity with O6-Benzylguanine abrogated the daily rhythm in sensitivity to TMZ in vitro by increasing sensitivity at both the peak and trough of Bmal1 expression. CONCLUSION: We conclude that chemotherapy with TMZ can be dramatically enhanced by delivering at the daily maximum of tumor Bmal1 expression and minimum of MGMT activity and that scoring MGMT methylation status requires controlling for time of day of biopsy.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Animais , Camundongos , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/patologia , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Dacarbazina/uso terapêutico , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , O(6)-Metilguanina-DNA Metiltransferase/genética , Estudos Retrospectivos , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Metilação , Enzimas Reparadoras do DNA/genética , Enzimas Reparadoras do DNA/metabolismo , Metilases de Modificação do DNA/genética , Metilases de Modificação do DNA/metabolismo , Metilação de DNA , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
Current mitochondrial DNA (mtDNA) haplogroup classification tools map reads to a single reference genome and perform inference based on the detected mutations to this reference. This approach biases haplogroup assignments towards the reference and prohibits accurate calculations of the uncertainty in assignment. We present HaploCart, a probabilistic mtDNA haplogroup classifier which uses a pangenomic reference graph framework together with principles of Bayesian inference. We demonstrate that our approach significantly outperforms available tools by being more robust to lower coverage or incomplete consensus sequences and producing phylogenetically-aware confidence scores that are unbiased towards any haplogroup. HaploCart is available both as a command-line tool and through a user-friendly web interface. The C++ program accepts as input consensus FASTA, FASTQ, or GAM files, and outputs a text file with the haplogroup assignments of the samples along with the level of confidence in the assignments. Our work considerably reduces the amount of data required to obtain a confident mitochondrial haplogroup assignment.
Assuntos
DNA Mitocondrial , Mitocôndrias , Humanos , DNA Mitocondrial/genética , Teorema de Bayes , Haplótipos/genética , Mitocôndrias/genética , MutaçãoRESUMO
Sex can be an important determinant of cancer phenotype, and exploring sex-biased tumor biology holds promise for identifying novel therapeutic targets and new approaches to cancer treatment. In an established isogenic murine model of glioblastoma (GBM), we discovered correlated transcriptome-wide sex differences in gene expression, H3K27ac marks, large Brd4-bound enhancer usage, and Brd4 localization to Myc and p53 genomic binding sites. These sex-biased gene expression patterns were also evident in human glioblastoma stem cells (GSCs). These observations led us to hypothesize that Brd4-bound enhancers might underlie sex differences in stem cell function and tumorigenicity in GBM. We found that male and female GBM cells exhibited sex-specific responses to pharmacological or genetic inhibition of Brd4. Brd4 knockdown or pharmacologic inhibition decreased male GBM cell clonogenicity and in vivo tumorigenesis while increasing both in female GBM cells. These results were validated in male and female patient-derived GBM cell lines. Furthermore, analysis of the Cancer Therapeutic Response Portal of human GBM samples segregated by sex revealed that male GBM cells are significantly more sensitive to BET (bromodomain and extraterminal) inhibitors than are female cells. Thus, Brd4 activity is revealed to drive sex differences in stem cell and tumorigenic phenotypes, which can be abrogated by sex-specific responses to BET inhibition. This has important implications for the clinical evaluation and use of BET inhibitors.
Assuntos
Proteínas de Ciclo Celular/metabolismo , Glioblastoma/metabolismo , Proteínas Nucleares/metabolismo , Fatores Sexuais , Fatores de Transcrição/metabolismo , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Expressão Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Glioblastoma/genética , Histonas/metabolismo , Humanos , Masculino , Camundongos , Proteínas Nucleares/fisiologia , Ligação Proteica , Proteínas Proto-Oncogênicas c-myc/metabolismo , Sequências Reguladoras de Ácido Nucleico/genética , Caracteres Sexuais , Fatores de Transcrição/fisiologia , Proteína Supressora de Tumor p53/metabolismoRESUMO
In humans, the combination of all sex-specific genetic, epigenetic, and hormonal influences of biologic sex produces different in vivo environments for male and female cells. We dissect how these influences of sex modify the pharmacokinetics and pharmacodynamics of multiple drugs and provide examples for common drugs acting on specific organ systems. We also discuss how gender of physicians and patients may influence the therapeutic response to drugs. We aim to highlight sex as a genetic modifier of the pharmacological response to drugs, which should be considered as a necessary step toward precision medicine that will benefit men and women. SIGNIFICANCE STATEMENT: This study discusses the influences of biologic sex on the pharmacokinetics and pharmacodynamics of drugs and provides examples for common drugs acting on specific organ systems. This study also discusses how gender of physicians and patients influence the therapeutic response to drugs.
Assuntos
Preparações Farmacêuticas , Caracteres Sexuais , Feminino , Humanos , Masculino , Medicina de PrecisãoRESUMO
The twin pandemics of COVID-19 and structural racism brought into focus health disparities and disproportionate impacts of disease on communities of color. Health equity has subsequently emerged as a priority. Recognizing that the future of health care will be informed by advanced information technologies including artificial intelligence (AI), machine learning, and algorithmic applications, the authors argue that to advance towards states of improved health equity, health information professionals need to engage in and encourage the conduct of research at the intersections of health equity, health disparities, and computational biomedical knowledge (CBK) applications. Recommendations are provided with a means to engage in this mobilization effort.
Assuntos
COVID-19 , Equidade em Saúde , Informática Médica , Humanos , Informática Médica/organização & administração , SARS-CoV-2 , Bibliotecas Médicas/organização & administração , Inteligência ArtificialRESUMO
Due to the complex nature of noncovalent interactions and their long-range effects, analyzing protein conformations using network theory can be enlightening. Protein Structure Networks (PSNs) provide a convenient formalism to study protein structures in relation to essential properties such as key residues for structural stability, allosteric communication, and the effects of modifications of the protein. PSNs can be defined according to very different principles, and the available tools have limitations in input formats, supported models, and version control. Other outstanding problems are related to the definition of network cutoffs and the assessment of the stability of the network properties. The protein science community could benefit from a common framework to carry out these analyses and make them easier to reproduce, reuse, and evaluate. We here provide two open-source software packages, PyInteraph2 and PyInKnife2, to implement and analyze PSNs in a reproducible and documented manner. PyInteraph2 interfaces with multiple formats for protein ensembles and incorporates different network models with the possibility of integrating them into a macronetwork and performing various downstream analyses, including hubs, connected components, and several other centrality measures, and visualizes the networks or further analyzes them thanks to compatibility with Cytoscape.PyInKnife2 that supports the network models implemented in PyInteraph2. It employs a jackknife resampling approach to estimate the convergence of network properties and streamline the selection of distance cutoffs. We foresee that the modular structure of the code and the supported version control system will promote the transition to a community-driven effort, boost reproducibility, and establish common protocols in the PSN field. As developers, we will guarantee the introduction of new functionalities and maintenance, assistance, and training of new contributors.
Assuntos
Proteínas , Software , Reprodutibilidade dos Testes , Proteínas/química , Conformação ProteicaRESUMO
Gastroesophageal reflux disease (GERD) is primarily diagnosed based on symptoms and response to a proton-pump inhibitor (PPI) trial. Gold standard testing requires an invasive endoscopic procedure, often with ambulatory pH monitoring. Salivary pepsin is a potential noninvasive modality for GERD diagnosis. This study aimed to assess diagnostic performance of salivary pepsin thresholds for GERD and determine optimal collection protocol of saliva in an external validation cohort. Over 10 months, adults with symptoms of GERD undergoing esophagogastroduodenoscopy with wireless pH-monitoring off PPI were enrolled. Saliva was self-collected by participants over 4 days across three different time points: fasting ante meridiem (AM), post-prandial, and bedtime (PM). Pepsin levels were calculated via Peptest. Pepsin variability and agreement were determined using linear mixed effects models and intraclass correlation. Validation of diagnostic threshold and performance characteristics were evaluated by receiver-operator curve analysis. Twenty participants enrolled in the study; 50% with physiologic acid exposure (acid exposure time < 4% no GERD) and 50% with elevated acid exposure (GERD). Mean pepsin concentrations were significantly lower in the AM (22.6 ± 25.2 ng/mL) compared to post-prandial (44.5 ± 36.7 ng/mL) and PM (55.4 ± 47.0 ng/mL). Agreement between pepsin concentrations across 3 days was substantial for AM samples (kappa 0.61), with lower agreement for post-prandial and PM samples. A single AM pepsin concentration of 25 ng/mL was 67% accurate for GERD with 56% sensitivity and 78% specificity. This validation study highlights fair accuracy and performance characteristics of a single fasting AM salivary pepsin concentration for the diagnosis of GERD.
Assuntos
Refluxo Gastroesofágico , Pepsina A , Adulto , Humanos , Pepsina A/análise , Sensibilidade e Especificidade , Refluxo Gastroesofágico/diagnóstico , Monitoramento do pH Esofágico , Saliva/química , Inibidores da Bomba de PrótonsRESUMO
Clinicians can encounter sex and gender disparities in diagnostic and therapeutic responses. These disparities are noted in epidemiology, pathophysiology, clinical manifestations, disease progression, and response to treatment. This Review discusses the fundamental influences of sex and gender as modifiers of the major causes of death and morbidity. We articulate how the genetic, epigenetic, and hormonal influences of biological sex influence physiology and disease, and how the social constructs of gender affect the behaviour of the community, clinicians, and patients in the health-care system and interact with pathobiology. We aim to guide clinicians and researchers to consider sex and gender in their approach to diagnosis, prevention, and treatment of diseases as a necessary and fundamental step towards precision medicine, which will benefit men's and women's health.
Assuntos
Causas de Morte , Nível de Saúde , Medicina de Precisão/normas , Distribuição por Sexo , Doença Aguda/epidemiologia , Betacoronavirus , COVID-19 , Doença Crônica/epidemiologia , Infecções por Coronavirus/epidemiologia , Feminino , Humanos , Masculino , Pandemias , Pneumonia Viral/epidemiologia , SARS-CoV-2 , Caracteres Sexuais , Fatores SexuaisRESUMO
Medulloblastoma, a common pediatric malignant central nervous system tumour, represent a small proportion of brain tumours in adults. Previously it has been shown that in adults, Sonic Hedgehog (SHH)-activated tumours predominate, with Wingless-type (WNT) and Group 4 being less common, but molecular risk stratification remains a challenge. We performed an integrated analysis consisting of genome-wide methylation profiling, copy number profiling, somatic nucleotide variants and correlation of clinical variables across a cohort of 191 adult medulloblastoma cases identified through the Medulloblastoma Advanced Genomics International Consortium. We identified 30 WNT, 112 SHH, 6 Group 3, and 41 Group 4 tumours. Patients with SHH tumours were significantly older at diagnosis compared to other subgroups (p < 0.0001). Five-year progression-free survival (PFS) for WNT, SHH, Group 3, and Group 4 tumours was 64.4 (48.0-86.5), 61.9% (51.6-74.2), 80.0% (95% CI 51.6-100.0), and 44.9% (95% CI 28.6-70.7), respectively (p = 0.06). None of the clinical variables (age, sex, metastatic status, extent of resection, chemotherapy, radiotherapy) were associated with subgroup-specific PFS. Survival among patients with SHH tumours was significantly worse for cases with chromosome 3p loss (HR 2.9, 95% CI 1.1-7.6; p = 0.02), chromosome 10q loss (HR 4.6, 95% CI 2.3-9.4; p < 0.0001), chromosome 17p loss (HR 2.3, 95% CI 1.1-4.8; p = 0.02), and PTCH1 mutations (HR 2.6, 95% CI 1.1-6.2; p = 0.04). The prognostic significance of 3p loss and 10q loss persisted in multivariable regression models. For Group 4 tumours, chromosome 8 loss was strongly associated with improved survival, which was validated in a non-overlapping cohort (combined cohort HR 0.2, 95% CI 0.1-0.7; p = 0.007). Unlike in pediatric medulloblastoma, whole chromosome 11 loss in Group 4 and chromosome 14q loss in SHH was not associated with improved survival, where MYCN, GLI2 and MYC amplification were rare. In sum, we report unique subgroup-specific cytogenetic features of adult medulloblastoma, which are distinct from those in younger patients, and correlate with survival disparities. Our findings suggest that clinical trials that incorporate new strategies tailored to high-risk adult medulloblastoma patients are urgently needed.
Assuntos
Neoplasias Cerebelares/genética , Meduloblastoma/genética , Adolescente , Adulto , Biomarcadores Tumorais/genética , Neoplasias Cerebelares/mortalidade , Neoplasias Cerebelares/patologia , Estudos de Coortes , Feminino , Humanos , Masculino , Meduloblastoma/mortalidade , Meduloblastoma/patologia , Intervalo Livre de Progressão , Fatores de Risco , Adulto JovemRESUMO
BACKGROUND/PURPOSE: Glioblastoma (GBM) is the most common primary malignant brain tumor. Sex has been shown to be an important prognostic factor for GBM. The purpose of this study was to develop and independently validate sex-specific nomograms for estimation of individualized GBM survival probabilities using data from 2 independent NRG Oncology clinical trials. METHODS: This analysis included information on 752 (NRG/RTOG 0525) and 599 (NRG/RTOG 0825) patients with newly diagnosed GBM. The Cox proportional hazard models by sex were developed using NRG/RTOG 0525 and significant variables were identified using a backward selection procedure. The final selected models by sex were then independently validated using NRG/RTOG 0825. RESULTS: Final nomograms were built by sex. Age at diagnosis, KPS, MGMT promoter methylation and location of tumor were common significant predictors of survival for both sexes. For both sexes, tumors in the frontal lobes had significantly better survival than tumors of multiple sites. Extent of resection, and use of corticosteroids were significant predictors of survival for males. CONCLUSIONS: A sex specific nomogram that assesses individualized survival probabilities (6-, 12- and 24-months) for patients with GBM could be more useful than estimation of overall survival as there are factors that differ between males and females. A user friendly online application can be found here- https://npatilshinyappcalculator.shinyapps.io/SexDifferencesInGBM/ .
Assuntos
Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Feminino , Glioblastoma/diagnóstico , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Masculino , Nomogramas , Prognóstico , Regiões Promotoras Genéticas , Modelos de Riscos ProporcionaisRESUMO
Gluten-related disorders, including celiac disease, wheat allergy, and nonceliac gluten sensitivity (NCGS), are increasingly reported worldwide. Celiac disease is caused by an immune-mediated reaction to ingested gluten in genetically susceptible persons. NCGS is largely a diagnosis of exclusion when other causes of symptoms have been ruled out. All patients with celiac disease should be referred to a registered dietitian nutritionist with expertise in celiac disease and a gastroenterologist who specializes in celiac disease and malabsorptive disorders, and they should remain on a strict gluten-free diet indefinitely. This article provides an overview of gluten- and wheat-related disorders.
Assuntos
Doença Celíaca , Biópsia , Doença Celíaca/diagnóstico , Doença Celíaca/dietoterapia , Doença Celíaca/epidemiologia , Diagnóstico Diferencial , Dieta Livre de Glúten , Suplementos Nutricionais , Endoscopia Gastrointestinal , Hospitalização , Humanos , Programas de Rastreamento , Educação de Pacientes como Assunto , Encaminhamento e ConsultaRESUMO
This project describes the creation of a single searchable resource during the pandemic, called the COVID-19 Best Evidence Front Door, with a primary goal of providing direct access to high-quality meta-analyses, literature syntheses, and clinical guidelines from a variety of trusted sources. The Front Door makes relevant evidence findable and accessible with a single search to aggregated evidence-based resources, optimizing time, discovery, and improved access to quality scientific evidence while reducing the burden of frontline health care providers and other knowledge-seekers in needing to separately identify, locate, and explore multiple websites.
Assuntos
COVID-19 , Pessoal de Saúde , Humanos , Pandemias , SARS-CoV-2RESUMO
BACKGROUND: Sex is recognized as a significant determinant of outcome among glioblastoma patients, but the relative prognostic importance of glioblastoma features has not been thoroughly explored for sex differences. METHODS: Combining multi-modal MR images, biomathematical models, and patient clinical information, this investigation assesses which pretreatment variables have a sex-specific impact on the survival of glioblastoma patients (299 males and 195 females). RESULTS: Among males, tumor (T1Gd) radius was a predictor of overall survival (HR = 1.027, p = 0.044). Among females, higher tumor cell net invasion rate was a significant detriment to overall survival (HR = 1.011, p < 0.001). Female extreme survivors had significantly smaller tumors (T1Gd) (p = 0.010 t-test), but tumor size was not correlated with female overall survival (p = 0.955 CPH). Both male and female extreme survivors had significantly lower tumor cell net proliferation rates than other patients (M p = 0.004, F p = 0.001, t-test). CONCLUSION: Despite similar distributions of the MR imaging parameters between males and females, there was a sex-specific difference in how these parameters related to outcomes.
Assuntos
Neoplasias Encefálicas/mortalidade , Glioblastoma/mortalidade , Imageamento por Ressonância Magnética/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Criança , Feminino , Seguimentos , Glioblastoma/patologia , Glioblastoma/terapia , Humanos , Interpretação de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Prognóstico , Estudos Retrospectivos , Fatores Sexuais , Taxa de Sobrevida , Adulto JovemRESUMO
Glioblastoma (GBM) is the most common malignant brain tumor in the United States. Incidence of GBM increases with age, and younger age-at-diagnosis is significantly associated with improved prognosis. While the relationship between candidate GBM risk SNPs and age-at-diagnosis has been explored, genome-wide association studies (GWAS) have not previously been stratified by age. Potential age-specific genetic effects were assessed in autosomal SNPs for GBM patients using data from four previous GWAS. Using age distribution tertiles (18-53, 54-64, 65+) datasets were analyzed using age-stratified logistic regression to generate p values, odds ratios (OR), and 95% confidence intervals (95%CI), and then combined using meta-analysis. There were 4,512 total GBM cases, and 10,582 controls used for analysis. Significant associations were detected at two previously identified SNPs in 7p11.2 (rs723527 [p54-63 = 1.50x10-9 , OR54-63 = 1.28, 95%CI54-63 = 1.18-1.39; p64+ = 2.14x10-11 , OR64+ = 1.32, 95%CI64+ = 1.21-1.43] and rs11979158 [p54-63 = 6.13x10-8 , OR54-63 = 1.35, 95%CI54-63 = 1.21-1.50; p64+ = 2.18x10-10 , OR64+ = 1.42, 95%CI64+ = 1.27-1.58]) but only in persons >54. There was also a significant association at the previously identified lower grade glioma (LGG) risk locus at 8q24.21 (rs55705857) in persons ages 18-53 (p18-53 = 9.30 × 10-11 , OR18-53 = 1.76, 95%CI18-53 = 1.49-2.10). Within The Cancer Genome Atlas (TCGA) there was higher prevalence of 'LGG'-like tumor characteristics in GBM samples in those 18-53, with IDH1/2 mutation frequency of 15%, as compared to 2.1% [54-63] and 0.8% [64+] (p = 0.0005). Age-specific differences in cancer susceptibility can provide important clues to etiology. The association of a SNP known to confer risk for IDH1/2 mutant glioma and higher prevalence of IDH1/2 mutation within younger individuals 18-53 suggests that more younger individuals may present initially with 'secondary glioblastoma.'
Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Glioblastoma/genética , Glioblastoma/patologia , Adolescente , Adulto , Fatores Etários , Idoso , Estudos de Casos e Controles , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Polimorfismo de Nucleotídeo Único , Adulto JovemRESUMO
Focused ultrasound (FUS) technology is reported to enhance the delivery of 64 Cu-integrated ultrasmall gold nanoclusters (64 Cu-AuNCs) across the blood-brain barrier (BBB) as measured by positron emission tomography (PET). To better define the optimal physical properties for brain delivery, 64 Cu-AuNCs with different surface charges are synthesized and characterized. In vivo biodistribution studies are performed to compare the individual organ uptake of each type of 64 Cu-AuNCs. Quantitative PET imaging post-FUS treatment shows site-targeted brain penetration, retention, and diffusion of the negative, neutral, and positive 64 Cu-AuNCs. Autoradiography is performed to compare the intrabrain distribution of these nanoclusters. PET Imaging demonstrates the effective BBB opening and successful delivery of 64 Cu-AuNCs into the brain. Of the three 64 Cu-AuNCs investigated, the neutrally charged nanostructure performs the best and is the candidate platform for future theranostic applications in neuro-oncology.
Assuntos
Barreira Hematoencefálica/diagnóstico por imagem , Barreira Hematoencefálica/metabolismo , Ouro/administração & dosagem , Nanopartículas Metálicas/administração & dosagem , Tomografia por Emissão de Pósitrons , Ultrassom/métodos , Animais , Nanopartículas Metálicas/ultraestrutura , Camundongos , Polietilenoglicóis/química , Propriedades de Superfície , Ácido Tióctico/química , Distribuição TecidualRESUMO
Sex differences in human health and disease can range from undetectable to profound. Differences in brain tumor rates and outcome are evident in males and females throughout the world and regardless of age. These observations indicate that fundamental aspects of sex determination can impact the biology of brain tumors. It is likely that optimal personalized approaches to the treatment of male and female brain tumor patients will require recognizing and understanding the ways in which the biology of their tumors can differ. It is our view that sex-specific approaches to brain tumor screening and care will be enhanced by rigorously documenting differences in brain tumor rates and outcomes in males and females, and understanding the developmental and evolutionary origins of sex differences. Here we offer such an integrative perspective on brain tumors. It is our intent to encourage the consideration of sex differences in clinical and basic scientific investigations.
Assuntos
Evolução Biológica , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/fisiopatologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Caracteres Sexuais , Proteína Supressora de Tumor p53/metabolismo , Neoplasias Encefálicas/diagnóstico , AMP Cíclico/metabolismo , Feminino , Humanos , Incidência , Masculino , Proteína do Retinoblastoma/metabolismo , Resultado do TratamentoRESUMO
OBJECTIVE: Children with neurofibromatosis-1 (NF1) are at risk for developing numerous nervous system abnormalities, including cognitive problems and brain tumors (optic pathway glioma). Currently, there are few prognostic factors that predict clinical manifestations or outcomes in patients, even in families with an identical NF1 gene mutation. In this study, we leveraged Nf1 genetically engineered mice (GEM) to define the potential role of sex as a clinically relevant modifier of NF1-associated neuronal dysfunction. METHODS: Deidentified clinical data were analyzed to determine the impact of sex on optic glioma-associated visual decline in children with NF1. In addition, Nf1 GEM were employed as experimental platforms to investigate sexually dimorphic differences in learning/memory, visual acuity, retinal ganglion cell (RGC) death, and Nf1 protein (neurofibromin)-regulated signaling pathway function (Ras activity, cyclic adenosine monophosphate [cAMP], and dopamine levels). RESULTS: Female patients with NF1-associated optic glioma were twice as likely to undergo brain magnetic resonance imaging for visual symptoms and 3× more likely to require treatment for visual decline than their male counterparts. As such, only female Nf1 GEM exhibited a decrement in optic glioma-associated visual acuity, shorter RGC axons, and attenuated cAMP levels. In contrast, only male Nf1 GEM showed spatial learning/memory deficits, increased Ras activity, and reduced dopamine levels. INTERPRETATION: Collectively, these observations establish sex as a major prognostic factor underlying neuronal dysfunction in NF1, and suggest that sex should be considered when interpreting future preclinical and clinical study results.