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Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that arise in connective tissue surrounding peripheral nerves. They occur sporadically in a subset of patients with neurofibromatosis type 1 (NF1). MPNSTs are highly aggressive, therapeutically resistant, and typically fatal. Using comparative transcriptome analysis, we identified CXCR4, a G-protein-coupled receptor, as highly expressed in mouse models of NF1-deficient MPNSTs, but not in nontransformed precursor cells. The chemokine receptor CXCR4 and its ligand, CXCL12, promote MPNST growth by stimulating cyclin D1 expression and cell-cycle progression through PI3-kinase (PI3K) and ß-catenin signaling. Suppression of CXCR4 activity either by shRNA or pharmacological inhibition decreases MPNST cell growth in culture and inhibits tumorigenesis in allografts and in spontaneous genetic mouse models of MPNST. We further demonstrate conservation of these activated molecular pathways in human MPNSTs. Our findings indicate a role for CXCR4 in NF1-associated MPNST development and identify a therapeutic target.
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Comunicação Autócrina , Quimiocina CXCL12/metabolismo , Neoplasias de Bainha Neural/metabolismo , Neoplasias de Bainha Neural/patologia , Receptores CXCR4/metabolismo , Ciclo Celular , Proliferação de Células , Transformação Celular Neoplásica , Células Cultivadas , Técnicas de Silenciamento de Genes , Humanos , Neurofibromatose 1/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de SinaisRESUMO
Hair differentiates from follicle stem cells through progenitor cells in the matrix. In contrast to stem cells in the bulge, the identities of the progenitors and the mechanisms by which they regulate hair shaft components are poorly understood. Hair is also pigmented by melanocytes in the follicle. However, the niche that regulates follicular melanocytes is not well characterized. Here, we report the identification of hair shaft progenitors in the matrix that are differentiated from follicular epithelial cells expressing transcription factor KROX20. Depletion of Krox20 lineage cells results in arrest of hair growth, confirming the critical role of KROX20+ cells as antecedents of structural cells found in hair. Expression of stem cell factor (SCF) by these cells is necessary for the maintenance of differentiated melanocytes and for hair pigmentation. Our findings reveal the identities of hair matrix progenitors that regulate hair growth and pigmentation, partly by creating an SCF-dependent niche for follicular melanocytes.
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Cabelo/citologia , Pigmentação/fisiologia , Fator de Células-Tronco/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Animais , Proteína 2 de Resposta de Crescimento Precoce/genética , Proteína 2 de Resposta de Crescimento Precoce/metabolismo , Regulação da Expressão Gênica , Cabelo/metabolismo , Queratinócitos/citologia , Queratinócitos/metabolismo , Melaninas/metabolismo , Camundongos , Pigmentação/genética , Fator de Células-Tronco/genéticaRESUMO
OBJECTIVE: The aim of this study is to evaluate neurofibromatosis type 1 (NF1) patients with whole-body MRI (WBMRI) to investigate the frequency of plexiform neurofibromas (pNFs), diffuse neurofibromas (dNFs), and malignant peripheral nerve sheath tumors (MPNSTs). MATERIALS AND METHODS: In this retrospective cross-sectional study, between the years 2015 and 2023, 83 consecutive patients with known NF1 underwent a total of 110 WBMRI screenings for MPNST using a standardized institutional protocol. The lesions are categorized as discrete lesions, pNFs, dNFs, and MPNSTs. Histopathology served as the reference standard for all MPNSTs. RESULTS: Among the 83 patients analyzed, 53 (64%) were women and 30 were men (36%) of ages 36.94±14.43 years (range, 15-66 years). Of the 83 patients, 33 have a positive family history of NF1 and positive genetic studies. Seven of 83 (8%) have only dNF, 20/83 (24%) have pNF, 28/83 (34%) have both dNF and pNF, and 28/83 (34%) have neither. Of the 83 patients, eight (9.6%) were diagnosed with nine total MPNSTs. Age range for patients with MPNSTs at time of diagnosis was 22-51, with an average age of 33.4 years. Only one MPNST (11%) developed from underlying pNF 4 years after WBMRI along the right bronchial tree. Three of eight (37.5%) patients with MPNST died within 5 years of pathologic diagnosis. CONCLUSION: This study suggests the absence of a predisposition for development of MPNST from pNFs and dNFs in the setting of NF1. As such, these lesions may not need special surveillance compared to discrete peripheral nerve sheath tumors.
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Neoplasias de Bainha Neural , Neurofibroma Plexiforme , Neurofibroma , Neurofibromatose 1 , Neurofibrossarcoma , Masculino , Humanos , Feminino , Adulto , Neurofibrossarcoma/diagnóstico por imagem , Neurofibrossarcoma/complicações , Estudos Transversais , Estudos Retrospectivos , Neurofibroma/diagnóstico por imagem , Neurofibromatose 1/diagnóstico por imagem , Neurofibromatose 1/complicações , Neurofibroma Plexiforme/diagnóstico por imagem , Neurofibroma Plexiforme/complicações , Neoplasias de Bainha Neural/diagnóstico por imagem , Imageamento por Ressonância MagnéticaRESUMO
Neurofibromatosis (NF) type I is a neuroectodermal and mesodermal dysplasia caused by a mutation of the neurofibromin tumor suppressor gene. Phenotypic features of NF1 vary, and patients develop benign peripheral nerve sheath tumors and malignant neoplasms, such as malignant peripheral nerve sheath tumor, malignant melanoma, and astrocytoma. Multiparametric whole-body MR imaging (WBMRI) plays a critical role in disease surveillance. Multiparametric MRI, typically used in prostate imaging, is a general term for a technique that includes multiple sequences, i.e. anatomic, diffusion, and Dixon-based pre- and post-contrast imaging. This article discusses the value of multiparametric WBMRI and illustrates the spectrum of whole-body lesions of NF1 in a single imaging setting. Examples of lesions include those in the skin (tumors and axillary freckling), soft tissues (benign and malignant peripheral nerve sheath tumors, visceral plexiform, and diffuse lesions), bone and joints (nutrient nerve lesions, non-ossifying fibromas, intra-articular neurofibroma, etc.), spine (acute-angled scoliosis, dural ectasia, intraspinal tumors, etc.), and brain/skull (optic nerve glioma, choroid plexus xanthogranuloma, sphenoid wing dysplasia, cerebral hamartomas, etc.). After reading this article, the reader will gain knowledge of the variety of lesions encountered with NF1 and their WBMRI appearances. Timely identification of such lesions can aid in accurate diagnosis and appropriate patient management.
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OBJECTIVES: Scoliosis is a common orthopedic problem in patients with neurofibromatosis 1 (NF1). Spinal deformities are found in 77% of all NF1 cases, with no widely accepted etiology. This study aimed to evaluate the frequency and types of scoliosis in NF1 patients using whole-body magnetic resonance imaging and to assess the association of intraspinal and paraspinal tumors with the imaging findings of scoliosis. METHODS: A total of 122 NF1 patients with whole-body magnetic resonance imaging were found from the electronic medical records. Ninety-seven cases that met the inclusion criteria were identified. All patients underwent 3-T magnetic resonance imaging with automated software fusion of the 3 sets of short TI inversion recovery and 3-dimensional T1-weighted coronal images. Frequency and location of scoliosis and intraspinal and paraspinal tumors were recorded. Patients with severe dystrophic-type scoliosis were separately identified, and Cobb angles were measured for all such cases. Association analysis was performed. A P value less than 0.05 was considered statistically significant. RESULTS: Ninety-seven patients with NF1 were evaluated. Two had prior spinal surgery and were excluded. The final sample of 95 patients included 33 (35%) men and 62 (65%) women with a mean ± SD body mass index of 25.82 (4.96) kg/m2. Of the 95 patients, 43 (45.3%) had scoliosis, 13 of 43 (30.2%) of which were severely angled. Of the 95 patients, 25 (26.3%) had locoregional tumor presence. Intraclass correlation for Cobb angles measured 0.99 (confidence interval, 0.98-1.0). Fisher exact test determined no association between scoliosis and presence of either paraspinal or intraspinal tumors (P = 0.485). There was also no association between the tumors and severe dystrophic scoliosis (P = 1.0). CONCLUSIONS: This study found no association between the presence of locoregional spinal tumors and scoliosis in NF1 patients. This work adds to the body of knowledge of scoliosis in NF1 patients and infers that presence of scoliosis should not mandate immediate search for locoregional spinal tumors.
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Neurofibromatose 1 , Escoliose , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética , Masculino , Neurofibromatose 1/complicações , Neurofibromatose 1/diagnóstico por imagem , Escoliose/diagnóstico por imagem , Imagem Corporal TotalRESUMO
Combat-related mild traumatic brain injury (cmTBI) is a leading cause of sustained physical, cognitive, emotional, and behavioral disabilities in Veterans and active-duty military personnel. Accurate diagnosis of cmTBI is challenging since the symptom spectrum is broad and conventional neuroimaging techniques are insensitive to the underlying neuropathology. The present study developed a novel deep-learning neural network method, 3D-MEGNET, and applied it to resting-state magnetoencephalography (rs-MEG) source-magnitude imaging data from 59 symptomatic cmTBI individuals and 42 combat-deployed healthy controls (HCs). Analytic models of individual frequency bands and all bands together were tested. The All-frequency model, which combined delta-theta (1-7 Hz), alpha (8-12 Hz), beta (15-30 Hz), and gamma (30-80 Hz) frequency bands, outperformed models based on individual bands. The optimized 3D-MEGNET method distinguished cmTBI individuals from HCs with excellent sensitivity (99.9 ± 0.38%) and specificity (98.9 ± 1.54%). Receiver-operator-characteristic curve analysis showed that diagnostic accuracy was 0.99. The gamma and delta-theta band models outperformed alpha and beta band models. Among cmTBI individuals, but not controls, hyper delta-theta and gamma-band activity correlated with lower performance on neuropsychological tests, whereas hypo alpha and beta-band activity also correlated with lower neuropsychological test performance. This study provides an integrated framework for condensing large source-imaging variable sets into optimal combinations of regions and frequencies with high diagnostic accuracy and cognitive relevance in cmTBI. The all-frequency model offered more discriminative power than each frequency-band model alone. This approach offers an effective path for optimal characterization of behaviorally relevant neuroimaging features in neurological and psychiatric disorders.
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Concussão Encefálica/diagnóstico por imagem , Concussão Encefálica/fisiopatologia , Distúrbios de Guerra/diagnóstico por imagem , Distúrbios de Guerra/fisiopatologia , Conectoma/normas , Aprendizado Profundo , Magnetoencefalografia/normas , Adulto , Conectoma/métodos , Humanos , Magnetoencefalografia/métodos , Masculino , Sensibilidade e Especificidade , Adulto JovemRESUMO
Combat-related mild traumatic brain injury (mTBI) is a leading cause of sustained impairments in military service members and veterans. Recent animal studies show that GABA-ergic parvalbumin-positive interneurons are susceptible to brain injury, with damage causing abnormal increases in spontaneous gamma-band (30-80 Hz) activity. We investigated spontaneous gamma activity in individuals with mTBI using high-resolution resting-state magnetoencephalography source imaging. Participants included 25 symptomatic individuals with chronic combat-related blast mTBI and 35 healthy controls with similar combat experiences. Compared with controls, gamma activity was markedly elevated in mTBI participants throughout frontal, parietal, temporal, and occipital cortices, whereas gamma activity was reduced in ventromedial prefrontal cortex. Across groups, greater gamma activity correlated with poorer performances on tests of executive functioning and visuospatial processing. Many neurocognitive associations, however, were partly driven by the higher incidence of mTBI participants with both higher gamma activity and poorer cognition, suggesting that expansive upregulation of gamma has negative repercussions for cognition particularly in mTBI. This is the first human study to demonstrate abnormal resting-state gamma activity in mTBI. These novel findings suggest the possibility that abnormal gamma activities may be a proxy for GABA-ergic interneuron dysfunction and a promising neuroimaging marker of insidious mild head injuries.
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Concussão Encefálica/fisiopatologia , Encéfalo/fisiopatologia , Ritmo Gama , Adulto , Concussão Encefálica/psicologia , Humanos , Magnetoencefalografia , Masculino , Vias Neurais , Testes Neuropsicológicos , GuerraRESUMO
Neurofibromatosis type 1 (NF1) is a hereditary tumour syndrome that predisposes to benign and malignant tumours originating from neural crest cells. Biallelic inactivation of the tumour-suppressor gene NF1 in glial cells in the skin, along a nerve plexus or in the brain results in the development of benign tumours: cutaneous neurofibroma, plexiform neurofibroma and glioma, respectively. Despite more than 40 years of research, only one medication was recently approved for treatment of plexiform neurofibroma and no drugs have been specifically approved for the management of other tumours. Work carried out over the past several years indicates that inhibiting different cellular signalling pathways (such as Hippo, Janus kinase/signal transducer and activator of transcription, mitogen-activated protein kinase and those mediated by sex hormones) in tumour cells or targeting cells in the microenvironment (nerve cells, macrophages, mast cells and T cells) might benefit NF1 patients. In this review, we outline previous strategies aimed at targeting these signalling pathways or cells in the microenvironment, agents that are currently in clinical trials, and the latest advances in basic research that could culminate in the development of novel therapeutics for patients with NF1.
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Terapia de Alvo Molecular , Neurofibromatose 1/genética , Neurofibromina 1/genética , Microambiente Tumoral/genética , Genes Supressores de Tumor , Humanos , Mutação/genética , Neurofibroma Plexiforme/tratamento farmacológico , Neurofibroma Plexiforme/genética , Neurofibromatose 1/patologia , Transdução de Sinais/genética , Pesquisa Translacional BiomédicaRESUMO
Peripheral nerve sheath tumors (PNSTs) account for ~ 5% of soft tissue neoplasms and are responsible for a wide spectrum of morbidities ranging from localized neuropathy to fulminant metastatic spread and death. MR imaging represents the gold standard for identification of these neoplasms, however, current anatomic MR imaging markers do not reliably detect or differentiate benign and malignant lesions, and therefore, biopsy or excision is required for definitive diagnosis. Diffusion-weighted MR imaging (DWI) serves as a useful tool in the evaluation and management of PNSTs by providing functional information regarding the degree of diffusion, while diffusion tensor imaging (DTI) aids in determining the directional information of predominant diffusion and has been shown to be particularly useful for pre-operative planning of these tumors by delineating healthy and pathologic fascicles. The article focuses on these important neurogenic lesions, highlighting the current utility of diffusion MR imaging and future directions including computerized radiomic analysis. KEY POINTS: ⢠Anatomic MRI is moderately accurate in differentiating benign from malignant PNST. ⢠Diffusion tensor imaging facilitates pre-operative planning of PNSTs by depicting neuropathy and tractography. ⢠Radiomics will likely augment current observer-based diagnostic criteria for PNSTs.
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Imagem de Difusão por Ressonância Magnética/métodos , Neoplasias de Bainha Neural/diagnóstico por imagem , Neoplasias de Tecidos Moles/diagnóstico por imagem , Imagem de Difusão por Ressonância Magnética/tendências , Imagem de Tensor de Difusão/métodos , Imagem de Tensor de Difusão/tendências , Humanos , Imageamento por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética/tendências , Imagem Multimodal/métodos , Imagem Multimodal/tendências , Neoplasias de Bainha Neural/terapia , Neoplasias de Tecidos Moles/terapiaRESUMO
Gas multisensor devices offer an effective approach to monitor air pollution, which has become a pandemic in many cities, especially because of transport emissions. To be reliable, properly trained models need to be developed that combine output from sensors with weather data; however, many factors can affect the accuracy of the models. The main objective of this study was to explore the impact of several input variables in training different air quality indexes using fuzzy logic combined with two metaheuristic optimizations: simulated annealing (SA) and particle swarm optimization (PSO). In this work, the concentrations of NO2 and CO were predicted using five resistivities from multisensor devices and three weather variables (temperature, relative humidity, and absolute humidity). In order to validate the results, several measures were calculated, including the correlation coefficient and the mean absolute error. Overall, PSO was found to perform the best. Finally, input resistivities of NO2 and nonmetanic hydrocarbons (NMHC) were found to be the most sensitive to predict concentrations of NO2 and CO.
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Cutaneous neurofibromas (cNF) are a nearly ubiquitous symptom of neurofibromatosis type 1 (NF1), a disorder with a broad phenotypic spectrum caused by germline mutation of the neurofibromatosis type 1 tumour suppressor gene (NF1). Symptoms of NF1 can include learning disabilities, bone abnormalities and predisposition to tumours such as cNFs, plexiform neurofibromas, malignant peripheral nerve sheath tumours and optic nerve tumours. There are no therapies currently approved for cNFs aside from elective surgery, and the molecular aetiology of cNF remains relatively uncharacterised. Furthermore, whereas the biallelic inactivation of NF1 in neoplastic Schwann cells is critical for cNF formation, it is still unclear which additional genetic, transcriptional, epigenetic, microenvironmental or endocrine changes are important. Significant inroads have been made into cNF understanding, including NF1 genotype-phenotype correlations in NF1 microdeletion patients, the identification of recurring somatic mutations, studies of cNF-invading mast cells and macrophages, and clinical trials of putative therapeutic targets such as mTOR, MEK and c-KIT. Despite these advances, several gaps remain in our knowledge of the associated pathogenesis, which is further hampered by a lack of translationally relevant animal models. Some of these questions may be addressed in part by the adoption of genomic analysis techniques. Understanding the aetiology of cNF at the genomic level may assist in the development of new therapies for cNF, and may also contribute to a greater understanding of NF1/RAS signalling in cancers beyond those associated with NF1. Here, we summarise the present understanding of cNF biology, including the pathogenesis, mutational landscape, contribution of the tumour microenvironment and endocrine signalling, and the historical and current state of clinical trials for cNF. We also highlight open access data resources and potential avenues for future research that leverage recently developed genomics-based methods in cancer research.
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Neurofibromatoses/genética , Neoplasias Cutâneas/genética , Animais , Genes da Neurofibromatose 1 , Genômica , Humanos , Mutação , Neurofibromatoses/metabolismo , Neurofibromatoses/patologia , Neurofibromatose 1/genética , Neurofibromatose 1/patologia , Neurofibromina 1/genética , Neurofibromina 1/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologiaRESUMO
Organized and hosted by the Children's Tumor Foundation (CTF), the Neurofibromatosis (NF) conference is the premier annual gathering for clinicians and researchers interested in neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN). The 2016 edition constituted a blend of clinical and basic aspects of NF research that helped in clarifying different advances in the field. The incorporation of next generation sequencing is changing the way genetic diagnostics is performed for NF and related disorders, providing solutions to problems like genetic heterogeneity, overlapping clinical manifestations, or the presence of mosaicism. The transformation from plexiform neurofibroma (PNF) to malignant peripheral nerve sheath tumor (MPNST) is being clarified, along with new management and treatments for benign and premalignant tumors. Promising new cellular and in vivo models for understanding the musculoskeletal abnormalities in NF1, the development of NF2 or SWN associated schwannomas, and clarifying the cells that give rise to NF1-associated optic pathway glioma were presented. The interaction of neurofibromin and SPRED1 was described comprehensively, providing functional insight that will help in the interpretation of pathogenicity of certain missense variants identified in NF1 and Legius syndrome patients. Novel promising imaging techniques are being developed, as well as new integrative and holistic management models for patients that take into account psychological, social, and biological factors. Importantly, new therapeutic approaches for schwannomas, meningiomas, ependymomas, PNF, and MPNST are being pursued. This report highlights the major advances that were presented at the 2016 CTF NF conference.
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Neurilemoma/diagnóstico , Neurilemoma/etiologia , Neurofibromatoses/diagnóstico , Neurofibromatoses/etiologia , Neurofibromatose 1/diagnóstico , Neurofibromatose 1/etiologia , Neurofibromatose 2/diagnóstico , Neurofibromatose 2/etiologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/etiologia , Animais , Gerenciamento Clínico , Modelos Animais de Doenças , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Técnicas de Diagnóstico Molecular , Neurilemoma/terapia , Neurofibromatoses/terapia , Neurofibromatose 1/terapia , Neurofibromatose 2/terapia , Neoplasias Cutâneas/terapia , Pesquisa Translacional BiomédicaRESUMO
OBJECTIVE: Segmentation of whole-body MRI (WBMRI) to assess the feasibility, quantitate the total tumor volume (tumor burden) in patients with neurofibromatosis type 1 (NF1) and examine associations with demographic, disease-related and anthropomorphic features. METHODS: A consecutive series of patients with NF1 underwent WBMRI and were reviewed for tumors. Tumors were segmented using a semiautomated software-based tool. Tumors were classified as superficial or deep and discrete or plexiform. Segmentation times were recorded. Segmentation yielded the quantity and tumor burden of superficial, internal and plexiform tumors. Correlations between segmentation data and demographic, disease-related and anthropomorphic features were examined. RESULTS: Fifteen patients were evaluated (42.3 ± 13.6 years, 10 female, 5 male). Segmentation times were a median of 30 min and yielded 2,328 tumors (1,582 superficial, 746 internal and 23 plexiform). One tumor was malignant. Tumor counts ranged from 14 to 397. Tumor burden ranged from 6.95 cm3 to 571 cm3. Individual tumor volume ranged from 0.0120 cm3 to 298 cm3. Significant correlation was found between the total volume of superficial tumors and height (ρ = 0.5966, p < 0.02). Male patients had higher overall tumor burdens (p < 0.05) and higher superficial tumor burden (p < 0.03). Patients with negative family history had more tumors (p < 0.05). CONCLUSION: Segmentation of WBMRI in patients with NF1 is feasible and elucidates meaningful relationships among disease phenotype, anthropomorphic and demographic features.
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Imageamento por Ressonância Magnética/métodos , Neurofibromatose 1/diagnóstico por imagem , Imagem Corporal Total , Adulto , Antropometria , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Masculino , Fenótipo , Carga TumoralRESUMO
We report the case of a patient with a long-standing history of extranodal, sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) and no evidence of original cutaneous involvement as well as a history of herpes zoster of the left flank with post-herpetic neuralgia who went on to develop multiple, round-to-oval, red-brown, atrophic macules and thin papules at the sites of herpes zoster scars on the left flank. Histopathology showed a dense nodular infiltrate of lymphocytes with some plasma cells and numerous large pale-staining histiocytes (S100+/CD68+), consistent with Rosai-Dorfman disease. This case showed exclusively cutaneous involvement, as demonstrated by otherwise normal physical examination, laboratory evaluation and imaging. This is the second reported case of Rosai-Dorfman disease occurring at the site of zoster scars, and to our knowledge this represents the first case report of cutaneous involvement of pre-existing Rosai-Dorfman disease via post-herpetic isotopic response (Wolf's isotopic response).
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Herpes Zoster , Histiocitose Sinusal/patologia , Dermatopatias/patologia , Cicatriz/patologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene that encodes neurofibromin, a RAS GTPase-activating protein. Inactivating NF1 mutations cause hyperactivation of RAS-mediated signaling, resulting in the development of multiple neoplasms, including malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are an aggressive tumor and the main cause of mortality in patients with NF1. MPNSTs are difficult to resect and refractory to chemo- and radiotherapy, and no molecular therapies currently exist. Immune checkpoint blockade (ICB) is an approach to treat inoperable, undruggable cancers like MPNST, but successful outcomes require an immune cell-rich tumor microenvironment. While MPNSTs are noninflamed "cold" tumors, here, we converted MPNSTs into T cell-inflamed "hot" tumors by activating stimulator of IFN genes (STING) signaling. Mouse genetic and human xenograft MPNST models treated with a STING agonist plus ICB exhibited growth delay via increased apoptotic cell death. This strategy offers a potential treatment regimen for MPNSTs.
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Imunoterapia , Proteínas de Membrana , Neurofibromatose 1 , Neurofibromina 1 , Microambiente Tumoral , Animais , Microambiente Tumoral/imunologia , Humanos , Camundongos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas de Membrana/imunologia , Neurofibromatose 1/genética , Neurofibromatose 1/patologia , Neurofibromatose 1/imunologia , Neurofibromatose 1/terapia , Neurofibromatose 1/metabolismo , Neurofibromina 1/genética , Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias de Bainha Neural/genética , Neoplasias de Bainha Neural/patologia , Neoplasias de Bainha Neural/terapia , Neoplasias de Bainha Neural/imunologia , Neoplasias de Bainha Neural/metabolismo , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Transdução de Sinais/imunologiaRESUMO
Nervous system tumors, particularly brain tumors, represent the most common tumors in children and one of the most lethal tumors in adults. Despite decades of research, there are few effective therapies for these cancers. Although human nervous system tumor cells and genetically engineered mouse models have served as excellent platforms for drug discovery and preclinical testing, they have limitations with respect to accurately recapitulating important aspects of the pathobiology of spontaneously arising human tumors. For this reason, attention has turned to the deployment of human stem cell engineering involving human embryonic or induced pluripotent stem cells, in which genetic alterations associated with nervous system cancers can be introduced. These stem cells can be used to create self-assembling three-dimensional cerebral organoids that preserve key features of the developing human brain. Moreover, stem cell-engineered lines are amenable to xenotransplantation into mice as a platform to investigate the tumor cell of origin, discover cancer evolutionary trajectories and identify therapeutic vulnerabilities. In this article, we review the current state of human stem cell models of nervous system tumors, discuss their advantages and disadvantages, and provide consensus recommendations for future research.
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Neoplasias Encefálicas , Células-Tronco Pluripotentes Induzidas , Criança , Humanos , Animais , Camundongos , Diferenciação Celular , Células-Tronco Pluripotentes Induzidas/patologia , Neoplasias Encefálicas/patologia , Encéfalo/patologia , MutaçãoRESUMO
This phase 2a trial investigated the efficacy of NFX-179 Topical Gel, a metabolically labile MEK inhibitor, in the treatment of cutaneous neurofibromas (cNFs) in neurofibromatosis type 1. Forty-eight participants were randomized to four treatment arms: NFX-179 Topical Gel 0.05%, 0.15%, and 0.5% or vehicle applied once daily to five target cNFs for 28 days. Treatment with NFX-179 Topical Gel resulted in a dose-dependent reduction in p-ERK levels in cNFs at day 28, with a 47% decrease in the 0.5% NFX-179 group compared to the vehicle (P = 0.0001). No local or systemic toxicities were observed during the treatment period, and systemic concentrations of NFX-179 remained below 1 ng/ml. In addition, 20% of cNFs treated with 0.5% NFX-179 Topical Gel showed a ≥50% reduction in volume compared to 6% in the vehicle group by ruler measurement with calculated volume (P = 0.021). Thus, NFX-179 Topical Gel demonstrated significant inhibition of MEK in cNF with excellent safety and potential therapeutic benefit.
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Neurofibromatose 1 , Inibidores de Proteínas Quinases , Neoplasias Cutâneas , Humanos , Neurofibromatose 1/tratamento farmacológico , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/efeitos adversos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neurofibroma/tratamento farmacológico , Neurofibroma/patologia , Neurofibroma/metabolismo , Adulto Jovem , Adolescente , Resultado do Tratamento , Administração Tópica , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismoRESUMO
Peripheral nerves have the potential to regenerate axons and reinnervate end organs. Chronic denervation and disturbed nerve regeneration are thought to contribute to peripheral neuropathy, pain, and pruritus in the skin. The capacity of denervated distal nerves to support axonal regeneration requires proliferation by Schwann cells, which guide regenerating axons to their denervated targets. However, adult peripheral nerve Schwann cells do not retain a growth-permissive phenotype, as is required to produce new glia. Therefore, it is believed that following injury, mature Schwann cells dedifferentiate to a progenitor/stem cell phenotype to promote axonal regrowth. In this study, we show that skin-derived precursors (SKPs), a recently identified neural crest-related stem cell population in the dermis of skin, are an alternative source of progenitors for cutaneous nerve regeneration. Using in vivo and in vitro three-dimensional cutaneous nerve regeneration models, we show that the SKPs are neurotropic toward injured nerves and that they have a full capacity to differentiate into Schwann cells and promote axon regeneration. The identification of SKPs as a physiologic source of progenitors for cutaneous nerve regeneration in the skin, where SKPs physiologically reside, has important implications for understanding early cellular events in peripheral nerve regeneration. It also provides fertile ground for the elucidation of intrinsic and extrinsic factors within the nerve microenvironment that likely play essential roles in cutaneous nerve homeostasis.
Assuntos
Derme/citologia , Regeneração Nervosa , Traumatismos dos Nervos Periféricos/terapia , Células de Schwann/citologia , Células-Tronco/citologia , Animais , Axônios/patologia , Diferenciação Celular , Derme/lesões , Derme/fisiologia , Camundongos , Neurônios Motores/fisiologia , Traumatismos dos Nervos Periféricos/patologia , Nervos Periféricos/fisiologia , Doenças do Sistema Nervoso Periférico/patologia , Doenças do Sistema Nervoso Periférico/terapia , Recuperação de Função Fisiológica , Células de Schwann/fisiologia , Transplante de Células-Tronco , Células-Tronco/fisiologia , Engenharia Tecidual , Alicerces TeciduaisRESUMO
Animal models represent the workhorse of the neuroscience field. Despite this, today, there is still no step-by-step protocol to dissect a complete rodent nervous system, nor is there a complete schematic representing it that is freely available. Only methods to harvest the brain, the spinal cord, a specific dorsal root ganglion, and the sciatic nerve (separately) are available. Here, we provide detailed pictures and a schematic of the central and peripheral murine nervous system. More importantly, we outline a robust procedure to perform its dissection. The 30 min pre-dissection step allows isolating the intact nervous system within the vertebra with muscles free of viscera and skin. A 2-4 h dissection follows it under a micro-dissection microscope to expose the spinal cord and the thoracic nerves, and finally peel the whole central and peripheral nervous system off the carcass. This protocol represents a significant step forward in studying the anatomy and pathophysiology of the nervous system globally. For example, the dissected dorsal root ganglions from a neurofibromatosis type I mice model can be further processed for histology to unravel changes in tumor progression.
Assuntos
Sistema Nervoso Periférico , Medula Espinal , Camundongos , Animais , Gânglios Espinais/cirurgia , Gânglios Espinais/patologia , Nervo Isquiático/cirurgia , EncéfaloRESUMO
Cutaneous neurofibromas (cNFs) are tumors that develop in more than 99% of individuals with neurofibromatosis type 1 (NF1). They develop in the dermis and can number in the thousands. cNFs can be itchy and painful and negatively impact self-esteem. There is no US Food and Drug Administration (FDA)-approved drug for their treatment. Here, we screen a library of FDA-approved drugs using a cNF cell model derived from human induced pluripotent stem cells (hiPSCs) generated from an NF1 patient. We engineer an NF1 mutation in the second allele to mimic loss of heterozygosity, differentiate the NF1+/- and NF1-/- hiPSCs into Schwann cell precursors (SCPs), and use them to screen a drug library to assess for inhibition of NF1-/- but not NF1+/- cell proliferation. We identify econazole nitrate as being effective against NF1-/- hiPSC-SCPs. Econazole cream selectively induces apoptosis in Nf1-/- murine nerve root neurosphere cells and human cNF xenografts. This study supports further testing of econazole for cNF treatment.