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1.
Brain Tumor Pathol ; 37(3): 100-104, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32535663

RESUMO

A subset of central nervous system neuroblastomas (CNS NB), rare primary embryonal CNS tumors, has been encompassed in CNS NB with FOXR2 activation (CNS NB-FOXR2) and usually shows the primitive neuronal architecture and occasional neurocytic differentiation. Here, we report a rare case of 3-year-old female with uncommon morphology of CNS embryonal tumor with FOXR2 activation presenting bidirectional differentiation to neurocytic small primitive cells and astrocytic spindle cells both of which are positive for synaptophysin and GFAP. Ultrastructural study also showed that there were presynaptic structure and intermediate filament in the tumor cells, suggesting glioneuronal differentiation. This case indicates the possibility of CNS neuroblastic tumor to differentiate neuronal and glial lineages.


Assuntos
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Fatores de Transcrição Forkhead/genética , Neuroblastoma/genética , Neuroblastoma/patologia , Neuroglia/patologia , Neurônios/patologia , Ativação Transcricional , Neoplasias Encefálicas/diagnóstico por imagem , Pré-Escolar , Feminino , Humanos , Imagem por Ressonância Magnética , Neuroblastoma/diagnóstico por imagem , Tomografia Computadorizada por Raios X
2.
Jpn J Clin Oncol ; 50(8): 839-846, 2020 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-32577751

RESUMO

NCYM is an antisense transcript of MYCN oncogene and promotes tumor progression. NCYM encodes a de novo protein whose open reading frame evolved from noncoding genomic regions in the ancestor of Homininae. Because of its topology, NCYM is always co-amplified with MYCN oncogene, and the mutual regulations between NCYM and MYCN maintain their expressions at high levels in MYCN-amplified tumors. NCYM stabilizes MYCN by inhibiting GSK3ß, whereas MYCN stimulates transcription of both NCYM and MYCN. NCYM mRNA and its noncoding transcript variants MYCNOS have been shown to stimulate MYCN expression via direct binding to MYCN promoter, indicating that both coding and noncoding transcripts of NCYM induce MYCN expression. In contrast to the noncoding functions of NCYM, NCYM protein also promotes calpain-mediated cleavage of c-MYC. The cleaved product called Myc-nick inhibits cell death and promotes cancer cell migration. Furthermore, NCYM-mediated inhibition of GSK3ß results in the stabilization of ß-catenin, which promotes aggressiveness of bladder cancers. These MYCN-independent functions of NCYM showed their clinical significance in MYCN-non-amplified tumors, including adult tumors. This year is the 30th anniversary of the identification of NCYM/MYCNOS gene. On this special occasion, we summarize the current understanding of molecular functions and the clinical significance of NCYM and discuss future directions to achieve therapeutic strategies targeting NCYM.


Assuntos
Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/genética , Neuroblastoma/genética , Reprogramação Celular/genética , Retroalimentação Fisiológica , Humanos , Neuroblastoma/patologia , Resultado do Tratamento
3.
Medicine (Baltimore) ; 99(25): e20853, 2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32569234

RESUMO

INTRODUCTION: Neuroblastoma (NB) with MYCN amplification has a poor prognosis and high mortality. The potential molecular biological relationship between clinical features and MYCN amplification should be explored. METHODS: NB patients were examined by fluorescence in situ hybridization (FISH) for MYCN amplification in the tumor mass or bone marrow samples to determine whether MYCN was amplified. A series of eleven MYCN-amplified NB patients were included. The age, primary site, tumor size, specific biomarkers, and invaded organs were analyzed. All patients accepted standardized treatment of surgery, chemotherapy, and radiotherapy. Progression-free survival (PFS) and overall survival (OS) were evaluated. RESULTS: The median age at diagnosis was 24 months. Nine patients (81.8%) were in stage IV, with high serum neuron-specific enolase (NSE) expression, normal urine vanillylmandelic acid (VMA) level and extensive metastases. All patients accepted a chemotherapy protocol with 8 to 10 cycles, and 9 patients (81.8%) were sensitive to the initial chemotherapy protocol. At the end of follow-up, four patients (36.3%) died with a median OS of 15 months. Five patients (45%) survived with a median PFS of 13 months. Two patients were still receiving chemotherapy. CONCLUSION: Given the effect of MYCN amplification on poor outcome in NB, novel treatments targeting MYCN should be developed for patients with NB.


Assuntos
Proteína Proto-Oncogênica N-Myc/metabolismo , Neuroblastoma/patologia , Pré-Escolar , Terapia Combinada , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Neuroblastoma/metabolismo , Neuroblastoma/mortalidade , Neuroblastoma/terapia , Análise de Sobrevida
4.
Life Sci ; 256: 117820, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32512012

RESUMO

Neuroblastoma (NB) is one of the most common malignant tumors in children. Chemotherapy resistance is one of the significant challenges in the treatment of high-risk NB patients, and it is necessary to search for new valid targets for NB treatment. This study aims to explore the possible role of PIF1 in NB by using bioinformatic analysis and downregulation of PIF1 with specific siRNA. Kyoto genome encyclopedia and R language based gene ontology was used to analyze the differentially expressed genes (DEGs) (including PIF1) when MYCN expression was silenced in NB cells. Analysis based on the R2 database showed a lower expression of PIF1 correlated with good prognosis in NB patients. Downregulation of MYCN expression by transfecting MYCN siRNA (#1, #2) into NB cells decreased the PIF1 expression at both mRNA and protein levels, while upregulation of MYCN expression by transfecting MYCN overexpressed plasmid increased the PIF1 expression. We further found that downregulation of PIF1 expression by transfecting PIF1 siRNA (#1, #2) into NB cells, increased the number of apoptotic cells, inhibited the cell survival, decreased the ability of cell migration and induced a cell cycle arrest at G1 phase. These data indicated that PIF1, as a potential new target of MYCN, maybe a novel target for NB treatment.


Assuntos
Apoptose/genética , Movimento Celular/genética , DNA Helicases/genética , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Biologia Computacional , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , Humanos , Neuroblastoma/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/genética , Regulação para Cima
5.
Mol Biol (Mosk) ; 54(2): 293-299, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32392199

RESUMO

Novel treatments for various types of malignant diseases are warranted. In this study, we evaluated JAK2 inhibitors (Janus kinase 2) for suppressing the growth of malignant neuroblastoma and glioblastoma cells as well as breast and non-small cell lung cancers. Neuroblastoma and glioblastoma cells are the most sensitive to the JAK2 inhibitor AG490. A study of the relative expression of receptors that can activate JAK2 suggests that cell line sensitivity to AG490 may be mediated by IL6-R, IL11-R and/or CSF1-R. AG490 enhances the effect of doxorubicin on neuroblastoma cells. Our findings suggest the possible relevance of JAK2 inhibitors for neuroblastoma therapy, especially in combination with doxorubicin.


Assuntos
Doxorrubicina/farmacologia , Janus Quinase 2/antagonistas & inibidores , Neuroblastoma/patologia , Ciclo Celular , Linhagem Celular Tumoral , Humanos , Janus Quinase 2/metabolismo , Fosforilação , Transdução de Sinais , Tirfostinas/farmacologia
6.
Cir. pediátr ; 33(2): 84-90, abr. 2020. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-190847

RESUMO

Objetivo: Comprobar la existencia de linfocitos T que incluyen linfocitos infiltrantes de tumor (TILs) en la sangre periférica (SP) de un modelo preclínico de neuroblastoma. Material y métodos: Utilizamos un modelo en ratones inmunodeficientes y otro en inmunocompetentes mediante inyección de suspensiones de la línea tumoral NB36769 con mutación de MYCN (TH-MYCN+). Se realizaron análisis por citometría de flujo (bazo, SP y tumor) y secuenciación del TCR-b en el ADN de muestras pareadas de tumor y SP. Resultados: En los ratones inmunodeficientes el componente principal en SP fue CD4: 83,1% (control) y 86,1% (tumor), siendo PD-1+ el 0,4 y el 0,3%. En el bazo obtuvimos un mayor porcentaje de linfocitos T PD-1+ que en SP, siendo similar en el control (6,5%) y en el ratón con tumor (6,2%), en subpoblación CD4+ exclusivamente. En los ratones inmunocompetentes observamos que la proporción de los 10 clones más frecuentes en los tumores constituía el 11,09% ± 2,83% del repertorio del TCR, mientras en SP representaba el 1,59% ± 0,59% (p = 0,024). Estos resultados sugieren un enriquecimiento de clonotipos dentro del tumor. De los 10 clones más frecuentes en las muestras tumorales, localizamos 9 también en la SP en dos ratones y 6 en el tercero. Además, encontramos secuencias compartidas por TILs de animales diferentes. Conclusiones: Nuestros resultados de inmunofenotipo y clonalidad apuntan a la existencia de linfocitos en SP que podrían contener TILs en un modelo experimental de neuroblastoma


Objective: To detect tumor-infiltrating lymphocytes (TILs) in the peripheral blood (PB) of a preclinical neuroblastoma model. Materials and methods: Two types of preclinical models - immuno-deficient mice and immunocompetent mice - were generated by injecting a cell suspension of neuroblastoma cell line NB36769 with MYCN gene (TH-MYCN+) overexpression. Spleen, tumor, and peripheral blood were studied using flow cytometry to detect PD-1+ T-cells. TCR-b immunose-quencing was performed in matched samples (tumor and peripheral blood). Results: Most PB T-cells of immunodeficient mice were CD4 (control: 83.1%; tumor: 86.1%), with a small proportion of PD-1+ T-cells (control: 0.4%; tumor: 0.3%). However, the percentage of PD-1+T-cells in the spleen was higher (control: 6.5%; tumor: 6.2%), and it was expressed in the CD4+ subset only. Regarding the TCR repertoire of immunocompetent mice, the propor-tion of the 10 most frequent sequences was significantly higher in tumors (11.09% ± 2.83%) than in the peripheral blood (1.59% ± 0.59%) (p = 0.024). These findings are suggestive of clonotype enrichment within the tumor. 9 out of the 10 most frequent tumor clones were identified in the matched peripheral blood sample in 2 mice, and 6 out of 10 in one mouse. In ad-dition, TILs with shared sequences from different animals were found. Conclusions: Our results in terms of immunophenotype and clon-ality suggest the presence of PB T-cells which could include TILs in a preclinical neuroblastoma model


Assuntos
Animais , Camundongos , Neuroblastoma/imunologia , Neuroblastoma/patologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos T/imunologia , Modelos Animais de Doenças , Hospedeiro Imunocomprometido , Citometria de Fluxo
7.
Pediatr Blood Cancer ; 67(6): e28267, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32307821

RESUMO

BACKGROUND: The treatment of high-risk neuroblastoma continues to present a formidable challenge to pediatric oncology. Previous studies have shown that Bromodomain and extraterminal (BET) inhibitors can inhibit MYCN expression and suppress MYCN-amplified neuroblastoma in vivo. Furthermore, alterations within RAS-MAPK (mitogen-activated protein kinase) signaling play significant roles in neuroblastoma initiation, maintenance, and relapse, and mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors demonstrate efficacy in subsets of neuroblastoma preclinical models. Finally, hyperactivation of RAS-MAPK signaling has been shown to promote resistance to BET inhibitors. Therefore, we examined the antitumor efficacy of combined BET/MEK inhibition utilizing I-BET726 or I-BET762 and trametinib in high-risk neuroblastoma. PROCEDURE: Utilizing a panel of genomically annotated neuroblastoma cell line models, we investigated the in vitro effects of combined BET/MEK inhibition on cell proliferation and apoptosis. Furthermore, we evaluated the effects of combined inhibition in neuroblastoma xenograft models. RESULTS: Combined BET and MEK inhibition demonstrated synergistic effects on the growth and survival of a large panel of neuroblastoma cell lines through augmentation of apoptosis. A combination therapy slowed tumor growth in a non-MYCN-amplified, NRAS-mutated neuroblastoma xenograft model, but had no efficacy in an MYCN-amplified model harboring a loss-of-function mutation in NF1. CONCLUSIONS: Combinatorial BET and MEK inhibition was synergistic in the vast majority of neuroblastoma cell lines in the in vitro setting but showed limited antitumor activity in vivo. Collectively, these data do not support clinical development of this combination in high-risk neuroblastoma.


Assuntos
Antineoplásicos/farmacologia , Benzodiazepinas/farmacologia , MAP Quinase Quinase 1/antagonistas & inibidores , Neuroblastoma/tratamento farmacológico , Proteínas/antagonistas & inibidores , Piridonas/farmacologia , Pirimidinonas/farmacologia , Animais , Apoptose , Proliferação de Células , Feminino , Humanos , Camundongos , Camundongos SCID , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Pediatr Blood Cancer ; 67(7): e28317, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32343886

RESUMO

Relapsed high-risk neuroblastoma has few effective therapies currently available or in development. Cabozantinib is an Food and Drug Administration approved multitargeted tyrosine kinase inhibitor for select adult malignancies with preclinical data suggesting efficacy against neuroblastoma. A safe and tolerable dose has been identified for children, but its efficacy remains unknown. We describe four children with relapsed metastatic neuroblastoma treated with cabozantinib. All four patients had extended disease control (two complete responsesfor >12 months, 2 stable disease >6 months) with manageable predictable toxicities requiring dose reduction in two patients. We discuss the potential for the use of cabozantinib in neuroblastoma.


Assuntos
Anilidas/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Neuroblastoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/uso terapêutico , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Masculino , Metástase Neoplásica , Recidiva Local de Neoplasia/patologia , Neuroblastoma/patologia , Prognóstico , Estudos Retrospectivos
9.
Life Sci ; 252: 117657, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-32289431

RESUMO

AIMS: The lncRNA distal-less homeobox 6 antisense 1 (DLX6-AS1) has been reported to be an oncogenic lncRNA in diverse malignant cancers; however, whether it has oncogenic role in neuroblastoma(NB) remain largely unknown. This study explored the expression status, function and potential mechanism of DLX6-AS1 in NB. MAIN METHOD: In the current study, a total of 70 human NB tissues and matched adjacent non-tumor tissues were collected. Quantitative PCR (qPCR) was performed to study the expression differences of DLX6-AS1 in tissues and NB cell lines. Proliferation, migration, invasion and EMT status of transfected NB cells were evaluated by WST-1 assay, colony formation unit assay, Transwell assay and qPCR, respectively. The interaction between DLX6-AS1 and its potential targets was confirmed by luciferase reporter assay. Xenograft models were established to evaluate tumor proliferation in vivo. KEY FINDING: We found that the expression of DLX6-AS1 was significantly increased in both NB tissues and cell lines, and elevated DLX6AS1 expression was positively correlated with advanced stage and poor survival. Proliferation rate, migration and invasion ability, as well as EMT process of NB cells was inhibited after DLX6-AS1 knockdown, meanwhile, the tumor growth in vivo was impaired after DLX6-AS1 inhibition. Further analysis showed that DLX6-AS1 regulates the expression of YAP1 by sponging miR-497-5p. DLX6-AS1 directly interacts with miR-497-5p and reduces the binding of miR-497-5p to YAP1 3'UTR, thus inhibiting the degradation of YAP1 by miR-497-5p. SIGNIFICANCE: This work demonstrates that DLX6-AS1 partially enhances the proliferation, migration and invasion abilities of NB cells through the miR-497-5p/YAP1 pathway, DLX6-AS1 might act as a promising therapeutic target for NB.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas de Homeodomínio/genética , MicroRNAs/genética , Neuroblastoma/genética , RNA Longo não Codificante/genética , Fatores de Transcrição/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Criança , Pré-Escolar , Progressão da Doença , Feminino , Técnicas de Silenciamento de Genes , Humanos , Lactente , Masculino , Invasividade Neoplásica/genética , Neuroblastoma/patologia
10.
Int J Mol Sci ; 21(7)2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-32218156

RESUMO

This study examined the biological activities of copaiba essential oil via measurement of its effects on signaling pathways in the SH-SY5Y neuronal cell line. Nanofluidic proteomic technologies were deployed to measure the phosphorylation of biomarker proteins within the signaling cascades. Interestingly, copaiba essential oil upregulated the pI3K/Akt/mTOR, MAPK, and JAK/STAT signaling pathways in neuronal cells. The effects of copaiba essential oil peaked at 30 min post-treatment, with a half-maximal effective concentration (EC50) of approximately 80 ng/mL. Treatment with cannabinoid receptor 2 (CB2) agonist AM1241 or the inverse agonist BML190 abrogated the regulatory effects of copaiba essential oil on the pI3K/Akt/mTOR signaling pathway. Surprisingly, copaiba essential oil also activated the apoptosis signaling pathway and reduced the viability of SH-SY5Y cells with an EC50 of approximately 400 ng/mL. Furthermore, ß-caryophyllene, a principal constituent of copaiba essential oil, downregulated the pI3K/Akt/mTOR signaling pathway. Taken together, the findings indicated that copaiba essential oil upregulated signaling pathways associated with cell metabolism, growth, immunity, and apoptosis. The biological activities of copaiba essential oil were determined to be fast acting, CB2 mediated, and dependent on multiple chemical constituents of the oil. Nanofluidic proteomics provided a powerful means to assess the biological activities of copaiba essential oil.


Assuntos
Fabaceae/química , Neuroblastoma/metabolismo , Óleos Voláteis/farmacologia , Óleos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Humanos , Neuroblastoma/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Serina-Treonina Quinases TOR/metabolismo
11.
Am Surg ; 86(2): 127-133, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32167055

RESUMO

Adrenal neuroblastoma (NB) is a relatively common malignancy in children. The Surveillance, Epidemiology, and End Results database was used to present demographic data and a survival analysis with the aim of making tumor management better. The Surveillance, Epidemiology, and End Results database was used to search pediatric patients (age ≤16 years) with NB from 2004 to 2013. The Kaplan-Meier method was used to calculate the overall survival. And, we used Cox regression analysis to determine hazard ratios for prognostic variables. Independent prognostic factors were selected into the nomogram to predict individual's three-, five-, and seven-year overall survival. The study included a total of 1870 pediatric patients with NB in our cohort. Overall, three-, five-, and seven-year survival rates for adrenal NB were 0.777, 0.701, and 0.665, respectively, whereas the rates for nonadrenal NB were 0.891, 0.859, and 0.832, respectively. The multivariate analysis identified age >1 year, no complete resection (CR)/CR, radiation, and regional/distant metastasis as independent predictors of mortality for adrenal NB. Concordance index of the nomogram was 0.665 (95% confidence interval, 0.627-0.703). Pediatric patients with adrenal NB have significantly worse survival than those with nonadrenal NB. Adrenal NB with age <1 year, treated with surgery, no radiation, and localized tumor leads to a better survival. There was no survival difference for patients to receive CR and no CR.


Assuntos
Neoplasias das Glândulas Suprarrenais/mortalidade , Neuroblastoma/mortalidade , Adolescente , Neoplasias das Glândulas Suprarrenais/patologia , Neoplasias das Glândulas Suprarrenais/cirurgia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Neuroblastoma/patologia , Neuroblastoma/cirurgia , Nomogramas , Prognóstico , Análise de Regressão , Programa de SEER/estatística & dados numéricos , Análise de Sobrevida , Taxa de Sobrevida , Fatores de Tempo
12.
Mol Biol (Mosk) ; 54(1): 128-136, 2020.
Artigo em Russo | MEDLINE | ID: mdl-32163396

RESUMO

Neuroinflammation plays a key role in the pathogenesis of neurodegenerative diseases. Microglial cells are the main immune cells of the central nervous system. On exposure to lipopolysaccharides (LPS, components of the cell wall of Gram-negative enterobacteria), microglia is activated to produce reactive oxygen species (ROS), cytokines, and inflammatory mediators, which may cause neuron death. Exogenous recombinant human heat shock protein 70 (HSP70) was tested for effect on the activation of human microglial and neuroblastoma cells in response to LPS from Escherichia coli. Experiments included cell cultivation separately and transferring the conditioned medium from A-172 microglial cells to SK-N-SH neuroblastoma cells to simulate the effect of microglia treated with LPS and/or HSP70. The levels of ROS, TNFα, and apoptosis in LPS-treated cells were estimated in the presence or absence of HSP70. HSP70 was found to reduce the LPS-induced ROS generation, TNFα production, apoptosis, and necrosis, in both separate cell cultures and neuroblastoma cells grown in the conditioned medium from microglial cells. Signaling pathways involving protein kinases p38MAPK, JNK, and PI3K were demonstrated to play an important role in HSP70-mediated protection of microglial and neuroblastoma cells from LPS-induced apoptosis and ROS production.


Assuntos
Meios de Cultivo Condicionados/química , Proteínas de Choque Térmico HSP70/farmacologia , Lipopolissacarídeos/toxicidade , Neuroblastoma/tratamento farmacológico , Neuroproteção/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Transdução de Sinais/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Humanos , Lipopolissacarídeos/imunologia , Microglia/efeitos dos fármacos , Microglia/imunologia , Microglia/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Espécies Reativas de Oxigênio/metabolismo
13.
Crit Rev Oncol Hematol ; 149: 102924, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32172225

RESUMO

Neuroblastoma is the most common extracranial solid tumor, arising from primitive sympathetic ganglion cells, in pediatric patients. The unique features of neuroblastoma include variable clinical behaviors, such as rapid progression to death and maturation to benign ganglioneuroma, followed by regression. Radiation therapy (RT) is usually administered to both the primary tumor bed and persistent metastatic sites after induction chemotherapy for high-risk neuroblastoma. RT to the tumor bed after surgical resection contributes significantly to local disease control and prevention of local relapse, confirming the role of RT. Palliative radiotherapy for metastatic neuroblastoma is also effective and safe and mainly provides symptomatic relief. The late side effects of RT in neuroblastoma patients include growth and developmental failure, hypothyroidism, gastrointestinal dysfunction, neurocognitive defects, pulmonary and cardiac abnormalities, infertility, and secondary cancers. In this article, we reviewed the role and toxicity of RT in neuroblastoma patients.


Assuntos
Quimioterapia de Indução/métodos , Neuroblastoma/radioterapia , Cuidados Paliativos/métodos , Neoplasias de Tecidos Moles/radioterapia , Criança , Irradiação Craniana , Humanos , Lactente , Recidiva Local de Neoplasia , Neuroblastoma/patologia , Neuroblastoma/secundário , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/secundário , Resultado do Tratamento
14.
Surgery ; 167(6): 969-977, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32122657

RESUMO

BACKGROUND: Neuroblastoma is the most common pediatric extracranial solid malignancy with limited effective treatment. We have shown that sustained-release, single drugs delivered locally through a silk-based biomaterial are effective in decreasing orthotopic neuroblastoma xenograft growth. We further optimized this approach and hypothesized that increasing doses of local chemotherapy or delivering 2 chemotherapeutic agents simultaneously inhibit additional tumor growth. METHODS: MYCN-amplified and non-MYCN-amplified neuroblastoma cells were treated with combinations of cisplatin, vincristine, doxorubicin, and etoposide to determine cytotoxicity and synergy. Drug-loaded silk material was created, and the amounts of drug released from the material over time were recorded. Murine orthotopic neuroblastoma xenografts were generated; tumors were implanted with single- or dual-agent chemotherapy-loaded silk. Ultrasound was used to monitor tumor growth, and tumor histology was evaluated. RESULTS: In vitro, vincristine/cisplatin combination was synergistic and significantly decreased cell viability relative to other combinations. Both drugs loaded into silk could be released effectively for over 2 weeks. Locally implanted vincristine/cisplatin silk induced increased tumor growth suppression compared with either agent alone in MYCN-amplified tumors (P < .05). The dose-dependent effect seen in MYCN-amplified tumors treated with combination therapy diminished at higher doses in non-MYCN-amplified tumors, with little benefit with doses >50 µg to 500 µg for vincristine-cisplatin, respectively. Tumor histology demonstrated tumor cell necrosis adjacent to drug-loaded silk material and presence of large cell neuroblastoma. CONCLUSION: Local delivery of sustained release chemotherapy can suppress tumor growth especially at high doses or with 2 synergistic drugs. Locally delivered dual therapy is a promising approach for future clinical testing.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Cisplatino/administração & dosagem , Doxorrubicina/administração & dosagem , Etoposídeo/administração & dosagem , Neuroblastoma/tratamento farmacológico , Vincristina/administração & dosagem , Animais , Preparações de Ação Retardada , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sistemas de Liberação de Medicamentos , Humanos , Camundongos , Transplante de Neoplasias , Neuroblastoma/patologia , Seda , Células Tumorais Cultivadas
15.
Medicine (Baltimore) ; 99(10): e19199, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32150058

RESUMO

Neuroblastoma is the most prevalent malignancy in infants characterized by heterogeneous prognosis. It is critical to stratify the risks for patients with neuroblastoma. To stratify the risks for neuroblastoma, clinical characteristics of neuroblastoma patients were retrieved from the Therapeutically Applicable Research to Generate Effective Treatment program. All patients were randomly sampled into the development and validation sets. Cox regression was used to construct a prediction nomogram. The discrimination and calibration capacity of the nomogram was assessed. Prognostic index (PI) was calculated and tested to evaluate the performance of the nomogram. This nomogram demonstrated reasonable discrimination and calibration capacity. The nomogram derived PI exhibited acceptable accuracy in predicting the prognosis for neuroblastoma patients. The overall survival rate was significantly different between the PI discriminated high and low-risk patient subgroups. In conclusion, besides traditional staging systems, some newly defined risk factors could be involved in risk stratification for patients with neuroblastoma. Our nomogram may aid the risk stratification for neuroblastoma patients.


Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Neuroblastoma/diagnóstico por imagem , Nomogramas , Área Sob a Curva , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/patologia , Pré-Escolar , China , Bases de Dados Factuais , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Imagem por Ressonância Magnética , Masculino , Estadiamento de Neoplasias , Neuroblastoma/mortalidade , Neuroblastoma/patologia , Prognóstico , Reprodutibilidade dos Testes , Risco , Análise de Sobrevida
16.
J Mol Biol ; 432(7): 2080-2098, 2020 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-32061932

RESUMO

The self-assembly of the 42-residue amyloid-ß peptide, Aß42, into fibrillar aggregates is associated with neuronal dysfunction and toxicity in Alzheimer's disease (AD) patient brains, suggesting that small molecules acting on this process might interfere with pathogenesis. Here, we present experimental evidence that the small molecule sclerotiorin (SCL), a natural product belonging to the group of azaphilones, potently delays both seeded and nonseeded Aß42 polymerization in cell-free assays. Mechanistic biochemical studies revealed that the inhibitory effect of SCL on fibrillogenesis is caused by its ability to kinetically stabilize small Aß42 oligomers. These structures exhibit low ß-sheet content and do not possess seeding activity, indicating that SCL acts very early in the amyloid formation cascade before the assembly of seeding-competent, ß-sheet-rich fibrillar aggregates. Investigations with NMR WaterLOGSY experiments confirmed the association of Aß42 assemblies with SCL in solution. Furthermore, using ion mobility-mass spectrometry, we observed that SCL directly interacts with a small fraction of Aß42 monomers in the gas phase. In comparison to typical amyloid fibrils, small SCL-stabilized Aß42 assemblies are inefficiently taken up into mammalian cells and have low toxicity in cell-based assays. Overall, these mechanistic studies support a pathological role of stable, ß-sheet-rich Aß42 fibrils in AD, while structures with low ß-sheet content may be less relevant.


Assuntos
Peptídeos beta-Amiloides/química , Amiloide/antagonistas & inibidores , Benzopiranos/farmacologia , Proliferação de Células , Neuroblastoma/tratamento farmacológico , Fragmentos de Peptídeos/química , Multimerização Proteica/efeitos dos fármacos , Peptídeos beta-Amiloides/metabolismo , Animais , Humanos , Camundongos , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Células PC12 , Fragmentos de Peptídeos/metabolismo , Conformação Proteica em Folha beta , Ratos , Células Tumorais Cultivadas
17.
Life Sci ; 246: 117399, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32032648

RESUMO

AIMS: Glioblastomas are highly aggressive brain tumors with a very poor survival rate. EEF1A2, the proto-oncogenic isoform of the EEF1A translation factor family, has been found to be overexpressed and promoting tumorigenesis in multiple cancers. Interestingly, recent studies reported reduced expression of this protein in brain tumors, drawing our attention to find the functional role and mechanism of this protein in brain tumor progression. MAIN METHODS: Using representative cell line as models, the role of EEF1A2 in cell proliferation, migration and invasion were assessed using MTS assay, scratch wound-healing assay, transwell migration and invasion assay, respectively. Activation of key signaling pathways was assessed using western blots and real-time PCR. Finally, using immunohistochemistry we checked the protein levels of EEF1A2 in CNS tumors. KEY FINDINGS: EEF1A2 was found to increase the proliferative, migratory and invasive properties of cell lines of both glial and neuronal origin. PI3K activation directly correlated with EEF1A2 levels. Protein levels of key EMT markers viz. Twist, Snail, and Slug were increased upon ectopic EEF1A2 expression. Furthermore, EEF1A2 was found to affect the expression levels of key inflammatory cytokines, growth factors and matrix metalloproteases. IHC analysis showed that EEF1A2 is upregulated in tumor tissues compared to normal tissue. SIGNIFICANCE: EEF1A2 acts as an oncogene in both neuronal and glial cells and triggers an EMT program via PI3K pathway. However, it shows enhanced expression in neuronal cells of the brain than the glial cells, which could explain the previously reported anomaly.


Assuntos
Neoplasias Encefálicas/metabolismo , Transição Epitelial-Mesenquimal , Fator 1 de Elongação de Peptídeos/metabolismo , Western Blotting , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Fator 1 de Elongação de Peptídeos/fisiologia , Reação em Cadeia da Polimerase em Tempo Real , Transcriptoma
18.
Pediatr Blood Cancer ; 67(5): e28153, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32072730

RESUMO

BACKGROUND: Image-guided percutaneous core needle biopsy (PCNB) is increasingly utilized to diagnose solid tumors. The objective of this study is to determine whether PCNB is adequate for modern biologic characterization of neuroblastoma. PROCEDURE: A multi-institutional retrospective study was performed by the Pediatric Surgical Oncology Research Collaborative on children with neuroblastoma at 12 institutions over a 3-year period. Data collected included demographics, clinical details, biopsy technique, complications, and adequacy of biopsies for cytogenetic markers utilized by the Children's Oncology Group for risk stratification. RESULTS: A total of 243 children were identified with a diagnosis of neuroblastoma: 79 (32.5%) tumor excision at diagnosis, 94 (38.7%) open incisional biopsy (IB), and 70 (28.8%) PCNB. Compared to IB, there was no significant difference in ability to accurately obtain a primary diagnosis by PCNB (95.7% vs 98.9%, P = .314) or determine MYCN copy number (92.4% vs 97.8%, P = .111). The yield for loss of heterozygosity and tumor ploidy was lower with PCNB versus IB (56.1% vs 90.9%, P < .05; and 58.0% vs. 88.5%, P < .05). Complications did not differ between groups (2.9 % vs 3.3%, P = 1.000), though the PCNB group had fewer blood transfusions and lower opioid usage. Efficacy of PCNB was improved for loss of heterozygosity when a pediatric pathologist evaluated the fresh specimen for adequacy. CONCLUSIONS: PCNB is a less invasive alternative to open biopsy for primary diagnosis and MYCN oncogene status in patients with neuroblastoma. Our data suggest that PCNB could be optimized for complete genetic analysis by standardized protocols and real-time pathology assessment of specimen quality.


Assuntos
Dosagem de Genes , Proteína Proto-Oncogênica N-Myc/genética , Neuroblastoma , Biópsia por Agulha , Pré-Escolar , Feminino , Humanos , Biópsia Guiada por Imagem , Masculino , Neuroblastoma/diagnóstico , Neuroblastoma/genética , Neuroblastoma/patologia , Medição de Risco
19.
Biochem Biophys Res Commun ; 523(3): 699-706, 2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-31948749

RESUMO

The WD repeat domain 5 (WDR5), also known as SWD3 and BIG-3, is often overexpressed in cancers, however its molecular function in cancer remains to be elucidated. In this study, we found that WDR5 promoted the proliferation and self-renewal of glioblastoma and neuroblastoma cells. The data from databases and Western blot assay showed that CARM1 is a downstream gene of WDR5-Myc axis. In addition, we observed that WDR5 promoted the binding of Myc to CARM1 promoter by interacting with Myc and inducing histone 3 lysine 4 trimethylation (H3K4me3). Dual luciferase reporter system indicated that Myc binds to the upstream region (-520 to -515) before transcription start site (TSS) of CARM1 promoter. These findings suggest a novel regulatory model for the proliferation and tumorigenesis of glioblastoma and neuroblastoma by WDR5-Myc axis.


Assuntos
Glioblastoma/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neuroblastoma/genética , Proteína-Arginina N-Metiltransferases/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Animais , Carcinogênese/genética , Carcinogênese/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/metabolismo , Glioblastoma/patologia , Histonas/metabolismo , Humanos , Camundongos Endogâmicos NOD , Camundongos SCID , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Mapas de Interação de Proteínas , Proteína-Arginina N-Metiltransferases/metabolismo , Transdução de Sinais , Ativação Transcricional
20.
Pediatr Surg Int ; 36(2): 137-143, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31925505

RESUMO

PURPOSE: The programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway has garnered much attention for its roles in clinical oncology. The aim of this study was to examine the clinical impact of the PD-L1 expression and tumor-infiltrating lymphocytes (TILs) on neuroblastoma. METHODS: We evaluated the PD-L1 expression and TIL status in 31 patients with neuroblastoma who underwent a biopsy or resection by an immunohistochemical analysis. Furthermore, we performed the serial analysis of the PD-L1 status before and after chemotherapy in 15 patients. RESULTS: Among the 31 cases, 11 (35%) showed a positive PD-L1 expression. The survival analysis showed a trend toward an association between PD-L1 positivity and a decreased overall survival. PD-L1 positivity tended to be associated with higher levels of tumor markers. In the serial analysis of the PD-L1 status, positivity was noted in 8 of 15 patients before chemotherapy and 6 after chemotherapy. Notably, all four patients with a positive PD-L1 status both before and after chemotherapy had recurrence, and 3 of them died during the follow-up period. CONCLUSION: Our findings suggest that the PD-L1 tumor expression might be a good biomarker for the treatment of neuroblastoma patients, especially for advanced neuroblastoma.


Assuntos
Antígeno B7-H1/biossíntese , Linfócitos do Interstício Tumoral/metabolismo , Neuroblastoma/metabolismo , Biomarcadores Tumorais/biossíntese , Biópsia , Feminino , Humanos , Imuno-Histoquímica , Lactente , Linfócitos do Interstício Tumoral/patologia , Masculino , Neuroblastoma/patologia
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