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1.
Front Immunol ; 15: 1427554, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39114662

RESUMO

Inflammatory myofibroblastic tumor (IMT) is a rare pathological entity first described in 1939. This lesion is most commonly found in the lungs, but cases involving other systems, such as the central nervous system known as intracranial IMT (IIMT), have also been reported. Diagnosis currently relies on pathological results due to the lack of characteristic imaging changes. Surgical resection is an effective treatment, though the disease is invasive and may recur. Previous literature has reported a high level of programmed death 1 (PD-1) expression in IMT tissues, suggesting that immunotherapy may be effective for this condition. In this case report, we present a middle-aged male who received PD-1 inhibitor and oncolytic adenovirus (Ad-TD-nsIL12) treatment after IIMT resection surgery. This successful approach provides a new direction for the treatment of IIMT.


Assuntos
Adenoviridae , Neoplasias Encefálicas , Inibidores de Checkpoint Imunológico , Terapia Viral Oncolítica , Humanos , Masculino , Terapia Viral Oncolítica/métodos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Encefálicas/terapia , Pessoa de Meia-Idade , Adenoviridae/genética , Vírus Oncolíticos/genética , Antígeno B7-H1/antagonistas & inibidores , Neoplasias de Tecido Muscular/terapia , Terapia Combinada , Resultado do Tratamento
2.
Life Sci ; 336: 122254, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-37977355

RESUMO

AIMS: Gliomas are the most common central nervous system malignancies, with limited therapeutic options and poor prognosis, which are primarily attributed to the "immune desert" microenvironment. Previously, we constructed a three-gene-deleted oncolytic adenovirus (Ad-TD) loaded with non-secreting interleukin-12 (nsIL-12), which could be amplified in tumor cells and induce immunity to suppress tumors. However, the effects of this oncolytic virus on gliomas and their immune microenvironment remain unclear. There is an urgent need for further research. MATERIALS AND METHODS: We constructed a Syrian hamster brain tumor model and demonstrated the efficacy and mechanism of the novel oncolytic virus in treating brain tumors through a series of in vitro and in vivo experiments. We investigated the efficacy and safety (the number of hamsters in each group is either 5 or 10) of the oncolytic virus treatment in Syrian hamsters using a virus-treated group, a control virus-treated group, and a blank control group. KEY FINDINGS: In vitro assays showed that Ad-TD-nsIL-12 could specifically proliferate in brain tumor cells which induce tumor cell apoptosis and intracellular expression of interleukin (IL)-12. Moreover, in vivo experiments demonstrated that Ad-TD-nsIL-12 could effectively inhibit the progression of brain tumors and prolong survival. Ad-TD-nsIL-12 significantly enhanced T-cell infiltration in the brain tumor microenvironment. SIGNIFICANCE: Ad-TD-nsIL-12 can inhibit glioma progression and increase T-cell infiltration in the tumor tissue, particularly infiltration by cytotoxic T cells (CD8+). Ad-TD-nsIL-12 can amplify and produce IL-12, inducing anti-glioma immune responses to inhibit tumor progression.


Assuntos
Neoplasias Encefálicas , Glioma , Terapia Viral Oncolítica , Vírus Oncolíticos , Cricetinae , Animais , Humanos , Vírus Oncolíticos/genética , Interleucina-12/genética , Microambiente Tumoral , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Glioma/terapia , Neoplasias Encefálicas/terapia , Mesocricetus
3.
Cancers (Basel) ; 15(22)2023 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-38001743

RESUMO

BACKGROUND: Based on the literature and data on its clinical trials, the incidence of venous thromboembolism (VTE) in patients undergoing neurosurgery has been 3.0%~26%. We used advanced machine learning techniques and statistical methods to provide a clinical prediction model for VTE after neurosurgery. METHODS: All patients (n = 5867) who underwent neurosurgery from the development and retrospective internal validation cohorts were obtained from May 2017 to April 2022 at the Department of Neurosurgery at the Sanbo Brain Hospital. The clinical and biomarker variables were divided into pre-, intra-, and postoperative. A univariate logistic regression (LR) was applied to explore the 67 candidate predictors with VTE. We used a multivariable logistic regression (MLR) to select all significant MLR variables of MLR to build the clinical risk prediction model. We used a random forest to calculate the importance of significant variables of MLR. In addition, we conducted prospective internal (n = 490) and external validation (n = 2301) for the model. RESULTS: Eight variables were selected for inclusion in the final clinical prediction model: D-dimer before surgery, activated partial thromboplastin time before neurosurgery, age, craniopharyngioma, duration of operation, disturbance of consciousness on the second day after surgery and high dose of mannitol, and highest D-dimer within 72 h after surgery. The area under the curve (AUC) values for the development, retrospective internal validation, and prospective internal validation cohorts were 0.78, 0.77, and 0.79, respectively. The external validation set had the highest AUC value of 0.85. CONCLUSIONS: This validated clinical prediction model, including eight clinical factors and biomarkers, predicted the risk of VTE following neurosurgery. Looking forward to further research exploring the standardization of clinical decision-making for primary VTE prevention based on this model.

4.
PeerJ ; 11: e15810, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37547724

RESUMO

Background: Gliomas are the most commonly-detected malignant tumors of the brain. They contain abundant long non-coding RNAs (lncRNAs), which are valuable cancer biomarkers. LncRNAs may be involved in genomic instability; however, their specific role and mechanism in gliomas remains unclear. LncRNAs that are related to genomic instability have not been reported in gliomas. Methods: The transcriptome data from The Cancer Genome Atlas (TCGA) database were analyzed. The co-expression network of genomic instability-related lncRNAs and mRNA was established, and the model of genomic instability-related lncRNA was identified by univariate Cox regression and LASSO analyses. Based on the median risk score obtained in the training set, we divided the samples into high-risk and low-risk groups and proved the survival prediction ability of genomic instability-related lncRNA signatures. The results were verified in the external data set. Finally, a real-time quantitative polymerase chain reaction assay was performed to validate the signature. Results: The signatures of 17 lncRNAs (LINC01579, AL022344.1, AC025171.5, LINC01116, MIR155HG, AC131097.3, LINC00906, CYTOR, AC015540.1, SLC25A21.AS1, H19, AL133415.1, SNHG18, FOXD3.AS1, LINC02593, AL354919.2 and CRNDE) related to genomic instability were identified. In the internal data set and Gene Expression Omnibus (GEO) external data set, the low-risk group showed better survival than the high-risk group (P < 0.001). In addition, this feature was identified as an independent risk factor, showing its independent prognostic value with different clinical stratifications. The majority of patients in the low-risk group had isocitrate dehydrogenase 1 (IDH1) mutations. The expression levels of these lncRNAs were significantly higher in glioblastoma cell lines than in normal cells. Conclusions: Our study shows that the signature of 17 lncRNAs related to genomic instability has prognostic value for gliomas and could provide a potential therapeutic method for glioblastoma.


Assuntos
Glioblastoma , Glioma , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , Prognóstico , Instabilidade Genômica/genética , Mutação , Glioma/genética
5.
J Craniofac Surg ; 34(2): 467-470, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36857564

RESUMO

OBJECTIVE: To investigate the surgical implications and morphologic type of upward bulging of the planum sphenoidale (PS) in anterior skull base meningiomas involving the tuberculum sellae area. METHODS: Between January 2014 and June 2021, 96 patients with anterior skull base meningiomas underwent surgery at the Sanbo Brain Hospital of Capital Medical University. A total of 96 patients with nonintracranial space-occupying lesions were selected as the control group. The height of upward bulging of the PS was measured and classified. The authors performed univariate and multivariate analyses to evaluate the rate and effects of upward bulging of the PS. RESULTS: The PS upward bulging rate was 23.00% versus 66.70% (P<0.001) between the control and meningioma groups. Multiple linear regression showed that it was correlated with the tumor midsagittal anteroposterior length (P=0.025) and the midsagittal height diameter (P=0.012). According to the height of PS upward bulging, it was divided into types 1, 2, and 3. The tumor gross-total resection rates were 96.9%, 92.3%, and 76.0%, respectively (P=0.042). CONCLUSIONS: Anterior skull base meningiomas involving the tuberculum sellae area can cause PS upward bulging, which lowers the tumor resection rate and should be considered while determining the treatment approach.


Assuntos
Neoplasias Meníngeas , Meningioma , Humanos , Encéfalo , Hospitais , Base do Crânio
6.
Biomed Pharmacother ; 157: 114037, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36427388

RESUMO

Glioblastoma (GBM) is one of the most aggressive primary malignant brain tumors. The major challenge is the lack of effective therapeutic drugs due to the blood-brain barrier (BBB) and tumor heterogeneity. Remdesivir (RDV), a new member of the nucleotide analog family, has previously been shown to have excellent antiviral effects and BBB penetration, and was predicted here to have anti-GBM effects. In vitro experiments, RDV significantly inhibited the growth of GBM cells, with IC50 values markedly lower than those of normal cell lines or the same cell lines treated with temozolomide. Moreover, in multiple mouse models, RDV not only distinctly inhibited the progression and improved the prognosis of GBM but also exhibited a promising biosafety profile, as manifested by the lack of significant body weight loss, liver or kidney dysfunction or organ structural damage after administration. Furthermore, we investigated the anti-GBM mechanism by RNA-seq and identified that RDV might induce apoptosis of GBM cells by enhancing endoplasmic reticulum (ER) stress and activating the PERK-mediated unfolded protein response. In conclusion, our results indicated that RDV might serve as a novel agent for GBM treatment by increasing ER stress and inducing apoptosis in GBM cells.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Camundongos , Animais , Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Estresse do Retículo Endoplasmático , Temozolomida , Resposta a Proteínas não Dobradas , Apoptose , Linhagem Celular Tumoral
7.
Front Oncol ; 12: 934159, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36452490

RESUMO

Background: Medulloblastoma (MB) is a malignant tumor associated with a poor prognosis in part due to a lack of effective detection methods. Extrachromosomal circular DNA (eccDNA) has been associated with multiple tumors. Nonetheless, little is currently known on eccDNA in MB. Methods: Genomic features of eccDNAs were identified in MB tissues and matched cerebrospinal fluid (CSF) and compared with corresponding normal samples using Circle map. The nucleotides on both sides of the eccDNAs' breakpoint were analyzed to understand the mechanisms of eccDNA formation. Bioinformatics analysis combined with the Gene Expression Omnibus (GEO) database identified features of eccDNA-related genes in MB. Lasso Cox regression model, univariate and multivariate Cox regression analysis, time-dependent ROC, and Kaplan-Meier curve were used to assess the potential diagnostic and prognostic value of the hub genes. Results: EccDNA was profiled in matched tumor and CSF samples from MB patients, and control, eccDNA-related genes enriched in MB were identified. The distribution of eccDNAs in the genome was closely related to gene density and the mechanism of eccDNA formation was evaluated. EccDNAs in CSF exhibited similar distribution with matched MB tissues but were differentially expressed between tumor and normal. Ten hub genes prominent in both the eccDNA dataset and the GEO database were selected to classify MB patients to either high- or low-risk groups, and a prognostic nomogram was thus established. Conclusions: This study provides preliminary evidence of the characteristics and formation mechanism of eccDNAs in MB and CSF. Importantly, eccDNA-associated hub genes in CSF could be used as diagnostic and prognostic biomarkers for MB.

8.
Mod Pathol ; 35(12): 1910-1920, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35804041

RESUMO

Loss of function in SMARCB1/INI1 has been observed in a group of malignancies collectively defined as SMARCB1/INI1-deficient neoplasms. Primary intracranial SMARCB1/INI1-deficient tumors in adults are extremely rare. We collected eight primary adult sellar SMARCB1/INI1-deficient tumors to study their clinicopathological and (epi)genetic characteristics. We performed a comprehensive assessment of the clinical, radiological, morphological and immunohistochemical features. FISH analysis for the SMARCB1 locus and target exome sequencing for 425 cancer relevant genes were performed. Furthermore, six bona fide proximal epithelioid sarcoma (PES), fourteen atypical teratoid/rhabdoid tumors (ATRT) in brain and five pediatric poorly differentiated chordomas (PDC) in the clivus were collected for comparative analysis of differential diagnostic maker expression and DNA methylation profile. The median age was 47.1 years, ranging from 26 to 73 years. On morphology, tumors were characterized by sheets of monomorphic larger epithelioid-like cells, in two cases with rhabdoid cells. "Stag-horn" vasculatures were observed in five cases. The loss of INI1 protein expression, co-expression of epithelial makers and mesenchymal markers were observed in all cases. CD34 expression was observed in six cases. Heterozygous deletion of SMARCB1/INI1 was confirmed using FISH in six cases. The results of target exome sequencing showed three patients harbored heterozygous point mutations in SMARCB1. The epigenetic features of the primary adult sellar SMARCB1/INI1-deficient tumors resembled the ATRT-MYC subgroup, but clustered apart from PES and PDC. Based on epigenetic characteristics, primary adult sellar SMARCB1/INI1-deficient tumors represent a subtype of ATRT with similar epigenetic characteristics of ATRT-MYC subgroup. Our findings suggest that DNA methylation profiling should be utilized for differential diagnosis for the majority of epithelioid sarcoma and (sellar) rhabdoid tumor.


Assuntos
Neoplasias Encefálicas , Cordoma , Tumor Rabdoide , Sarcoma , Humanos , Tumor Rabdoide/patologia , Proteína SMARCB1/genética , Proteína SMARCB1/metabolismo , Sarcoma/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/diagnóstico , Diagnóstico Diferencial
9.
Front Oncol ; 12: 789283, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35311131

RESUMO

N6-methyladenosine (m6A) modification is the most abundant modification in long noncoding RNAs (lncRNAs). Current studies have shown that the abnormal expression of m6A-related genes is closely associated with the tumorigenesis and progression of glioma. However, the role of m6A-related lncRNAs in glioma development is still unclear. Herein, we screened 566 m6A-related lncRNAs in glioma from The Cancer Genome Atlas (TCGA) database. The expression pattern of these lncRNAs could cluster samples into two groups, in which various classical tumor-related functions and the tumor immune microenvironment were significantly different. Subsequently, a nine-factor m6A-related lncRNA prognostic signature (MLPS) was constructed by using a LASSO regression analysis in the training set and was validated in the test set and independent datasets. The AUC values of the MLPS were 0.881, 0.918 and 0.887 for 1-, 3- and 5-year survival in the training set, respectively, and 0.856, 0.916 and 0.909 for 1-, 3-, and 5-year survival in the test set, respectively. Stratification analyses of the MLPS illustrated its prognostic performance in gliomas with different characteristics. Correlation analyses showed that the infiltrations of monocytes and tumor-associated macrophages (TAMs) were significantly relevant to the risk score in the MLPS. Moreover, we detected the expression of four MLPS factors with defined sequences in glioma and normal cells by using RT-PCR. Afterwards, we investigated the functions of LNCTAM34A (one of the MLPS factors) in glioma cells, which have rarely been reported. Via in vitro experiments, LNCTAM34A was demonstrated to promote the proliferation, migration and epithelial-mesenchymal transition (EMT) of glioma cells. Overall, our study revealed the critical role of m6A-related lncRNAs in glioma and elucidated that LNCTAM34A could promote glioma proliferation, migration and EMT.

10.
Front Cell Dev Biol ; 9: 717182, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35127693

RESUMO

Glioma is the most common tumor with the worst prognosis in the central nervous system. Current studies showed that glucose metabolism could affect the malignant progression of tumors. However, the study on the dysregulation of glucose metabolism in glioma is still limited. Herein, we firstly screened 48 differentially expressed glucose metabolism-related genes (DE-GMGs) by comparing glioblastomas to low-grade gliomas. Then a glucose metabolism-related gene (GMG)-based model (PC, lactate dehydrogenase A (LDHA), glucuronidase beta (GUSB), galactosidase beta 1 (GLB1), galactose mutarotase (GALM), or fructose-bisphosphatase 1 (FBP1)) was constructed by a protein-protein interaction (PPI) network and Lasso regression. Thereinto, the high-risk group encountered a worse prognosis than the low-risk group, and the M2 macrophage was positively relevant to the risk score. Various classical tumor-related functions were enriched by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Since protein GALM was rarely studied in glioma, we detected high expression of GALM by western blot and immunohistochemistry in glioma tissues. And experiments in vitro showed that GALM could promote the epithelial-to-mesenchymal transition (EMT) process of glioma cells and could be regulated by TNFAIP3 in glioma cells. Overall, our study revealed the critical role of glucose metabolism in the prognosis of patients with glioma. Furthermore, we demonstrated that GALM was significantly related to the malignancy of glioma and could promote glioma cells' EMT process.

11.
J Neuropathol Exp Neurol ; 79(11): 1183-1192, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-33085976

RESUMO

Chordoid gliomas (CG) of the third ventricle are characterized by chordoid and glial features, but the extent of histological variations across CG is not fully understood. Herein, we report 16 consecutive cases of CG. All 16 patients had histories of headache and vision loss; their median age was 41.7 years at the surgery. Histological examination revealed typical features of CG, including cords of epithelioid cells within the mucinous stroma and lymphoplasmacytic infiltration. Two cases exhibited atypical histological features including histiocyte-like cells. PRKCA mutation was found in 14 cases, including the 2 with histiocytic features. BRAFV600E mutation was found only in the 2 cases with histiocytic features. The patients underwent gross total tumor resection without radiotherapy or chemotherapy. Three patients died between 1 and 4 months postsurgery. Only one had a recurrence. Eleven were alive at the most recent follow-up (range: 2-58 months). These data indicate that PRKCA mutation was a good diagnostic marker for CG and additionally suggest that histiocyte-like features can be present in CG in association with BRAF mutations.


Assuntos
Neoplasias do Plexo Corióideo/genética , Glioma/genética , Proteína Quinase C-alfa/genética , Proteínas Proto-Oncogênicas B-raf/genética , Adolescente , Adulto , Neoplasias do Plexo Corióideo/patologia , Feminino , Glioma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Terceiro Ventrículo/patologia
12.
Neurol India ; 68(5): 1203-1206, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33109877

RESUMO

Trochlear nerve cavernous hemangioma (CH) is a rare disease. There have been only five such cases reported in the world literature till date. The authors report a case of trochlear nerve CH in the Asian population and review the relevant literature. A 49-year-old Asian woman presented with gradually worsening double vision for 6 years. Physical examination identified a complete paralysis of left trochlear nerve. In imaging, a circular lesion measuring about 1 cm in diameter was found in the left ambient cistern. The lesion was completely excised through the left-side subtemporal approach, with a diagnosis of trochlear nerve CH confirmed by pathological examination. Further nerve anastomosis was not adopted, and the patient remained clinically stable in a two years' follow-up. This report provides more information about the history characteristics, imaging features, and surgical treatment strategies for trochlear nerve CH.


Assuntos
Neoplasias dos Nervos Cranianos , Hemangioma Cavernoso , Neoplasias dos Nervos Cranianos/cirurgia , Diplopia , Feminino , Hemangioma Cavernoso/diagnóstico por imagem , Hemangioma Cavernoso/cirurgia , Humanos , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Procedimentos Neurocirúrgicos , Nervo Troclear
13.
Aging (Albany NY) ; 12(11): 10275-10289, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32491994

RESUMO

Glioblastoma (GBM) generally has a dismal prognosis, and it is associated with a poor quality of life as the disease progresses. However, the development of effective therapies for GBM has been deficient. Ubiquitin-conjugating enzyme E2T (UBE2T) is a member of the E2 family in the ubiquitin-proteasome pathway and a vital regulator of tumour progression, but its role in GBM is unclear. In this study, we aimed to clarify the role of UBE2T in GBM. Bioinformatics analysis identified UBE2T as an independent risk factor for gliomas. Immunohistochemistry was used to measure UBE2T expression in GBM and normal tissue samples obtained from patients with GBM. The effects of UBE2T on GBM cell invasion and migration were analysed using the Transwell assay. BALB/c nude mice were used for the in vivo assays. Immunoblotting and immunoprecipitation were performed to determine the molecular mechanisms. UBE2T was highly expressed in GBM tissues, and its expression was linked to a poor prognosis. In vitro, depletion of UBE2T significantly suppressed cell invasion and migration. Moreover, UBE2T depletion suppressed the growth of GBM subcutaneous tumours in vivo. Further experiments revealed that UBE2T suppressed invasion and migration by regulating epithelial- mesenchymal transition (EMT) via stabilising GRP78 in GBM cells. We uncovered a novel UBE2T/GRP78/EMT regulatory axis that modulates the malignant progression and recurrence of GBM, indicating that the axis might be a valuable therapeutic target.


Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , Proteínas de Choque Térmico/metabolismo , Recidiva Local de Neoplasia/patologia , Enzimas de Conjugação de Ubiquitina/metabolismo , Animais , Encéfalo/patologia , Linhagem Celular Tumoral , Proliferação de Células , Biologia Computacional , Conjuntos de Dados como Assunto , Chaperona BiP do Retículo Endoplasmático , Transição Epitelial-Mesenquimal , Humanos , Imuno-Histoquímica , Camundongos , Invasividade Neoplásica/patologia , Prognóstico , Estabilidade Proteica , RNA-Seq , Fatores de Risco , Ubiquitinação , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Nat Commun ; 11(1): 2506, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32427851

RESUMO

The genetic basis and corresponding clinical relevance of prolactinomas remain poorly understood. Here, we perform whole genome sequencing (WGS) on 21 patients with prolactinomas to detect somatic mutations and then validate the mutations with digital polymerase chain reaction (PCR) analysis of tissue samples from 227 prolactinomas. We identify the same hotspot somatic mutation in splicing factor 3 subunit B1 (SF3B1R625H) in 19.8% of prolactinomas. These patients with mutant prolactinomas display higher prolactin (PRL) levels (p = 0.02) and shorter progression-free survival (PFS) (p = 0.02) compared to patients without the mutation. Moreover, we identify that the SF3B1R625H mutation causes aberrant splicing of estrogen related receptor gamma (ESRRG), which results in stronger binding of pituitary-specific positive transcription factor 1 (Pit-1), leading to excessive PRL secretion. Thus our study validates an important mutation and elucidates a potential mechanism underlying the pathogenesis of prolactinomas that may lead to the development of targeted therapeutics.


Assuntos
Fosfoproteínas/genética , Prolactinoma/genética , Fatores de Processamento de RNA/genética , Adulto , Feminino , Humanos , Masculino , Mutação , Fosfoproteínas/metabolismo , Intervalo Livre de Progressão , Prolactina/genética , Prolactina/metabolismo , Prolactinoma/metabolismo , Prolactinoma/mortalidade , Fatores de Processamento de RNA/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Fator de Transcrição Pit-1/genética , Fator de Transcrição Pit-1/metabolismo , Adulto Jovem
15.
J Neurooncol ; 147(2): 327-337, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32170633

RESUMO

INTRODUCTION: Glioblastoma multiforme (GBM) is one of the most devastating brain malignancies worldwide and is considered to be incurable. However, the mechanisms underlying its aggressiveness remain unclear. METHODS: The expression of ADAM17 in tissue samples was detected by immunohistochemistry. Knockdown and rescue experiments were used to demonstrate the regulatory effect of ADAM17 on the invasion ability of GBM cells. Western Blot and qPCR were used to detect the expression of related proteins and RNAs. Moreover, a luciferase reporter assay was performed to verify whether miR-145 directly binds to the 3'-UTR of ADAM17. RESULTS: We revealed that ADAM17 was overexpressed in GBM tissues and correlated positively with poor prognosis. The knockdown of ADAM17 obviously suppressed the invasiveness of GBM cell lines. Furthermore, we found that knockdown of ADAM17 decreased activation of EGFR/Akt/C/EBP-ß signaling, and consequently upregulated miR-145 expression in GBM cell lines. Notably, miR-145 directly targeted the ADAM17 3'-UTR and suppressed expression levels of ADAM17. CONCLUSIONS: Our findings define an ADAM17/EGFR/miR-145 feedback loop that drives the GBM invasion. Reciprocal regulation between ADAM17 and miR-145 results in aberrant activation of EGFR signaling, suggesting that inhibition of ADAM17 expression can be an ideal therapeutic strategy for the treatment of GBM.


Assuntos
Proteína ADAM17/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/patologia , Glioblastoma/patologia , MicroRNAs/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína ADAM17/genética , Apoptose , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Movimento Celular , Proliferação de Células , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Invasividade Neoplásica , Prognóstico , Proteínas Proto-Oncogênicas c-akt/genética , Taxa de Sobrevida , Células Tumorais Cultivadas
16.
Medicine (Baltimore) ; 98(34): e16652, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31441839

RESUMO

INTRODUCTION: Tumors of the pineal region are rare, and metastatic carcinoma occurring in the pineal region is extremely rare. No previous reports have described pineal region metastasis with intraventricular seeding. PATIENT CONCERNS: We report a case of a 51-year-old woman presented with a 1-week history of severe headache, nausea, and vomiting. Imaging examination revealed 2 lesions in the pineal region and the right lateral ventricle. DIAGNOSIS: Pinealocytoma or germinoma was considered as the preoperative diagnosis. The postoperative pathological diagnosis was small cell neuroendocrine carcinoma. After bronchoscopic biopsy, small cell lung cancer was confirmed. INTERVENTIONS: A right frontal craniotomy and a translateral ventricle approach were performed to remove 2 lesions completely. And regular radiotherapy and chemotherapy were initiated after surgery. OUTCOMES: The patient was discharged from the hospital 2 weeks after operation and went to another cancer hospital for bronchoscopic biopsy, radiotherapy, and chemotherapy. Finally, the patient died 2 years after surgical treatment. CONCLUSION: Metastatic tumors of the pineal region are very rare. For patients with pineal lesions, a diagnosis of a metastatic tumor should be considered. Retrograde cerebrospinal fluid circulation might be the reason for a secondary metastasis.


Assuntos
Neoplasias Pulmonares/patologia , Pinealoma/secundário , Carcinoma de Pequenas Células do Pulmão/patologia , Diagnóstico Diferencial , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Pinealoma/cirurgia
17.
Cancer Manag Res ; 11: 5949-5959, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31308738

RESUMO

Purpose: The relationship of clinical results and survival analysis of operative patients with petroclival meningioma (PCM) was studied. Patients and methods: Data from a total of 176 PCM patients receiving surgical resection were retrospectively collected. Follow-up was conducted through outpatient review by reexamination telephone calls and letters. Clinical outcomes, survival, and Karnofsky Performance Scale (KPS) data were analyzed. Results: Seventy-two percent of patients (127/176) received only surgery, 8.5% (15/176) received surgery and adjuvant radiation therapy (RT) (surgery + RT), and 19.3% (34/176) received surgery and adjuvant gamma knife surgery (GKS) (surgery + GKS). Gross total resection (GTR) was performed in 34.7% of patients (61/176), subtotal resection (STR) in 58.0% (102/176), and partial resection (PR) in 7.4% (13/176). Recent follow-up KPS was higher than preoperative (80 vs 70, P<0.05) and postoperative KPS (80 vs 70, P<0.05). Cumulative survival was the same for 3, 5, 7, and 9 years, ie, 95%, and mean survival time (MST) was (110.83±2.55) months (95% CI: 105.83-115.83). Recurrence/progression (R/P)-free survival was 88.9%, 86.9%, 71.1% and 71.1%, respectively for 3, 5, 7, and 9 years, and MST was (100.58±3.82) months (95% CI: 93.11-108.06). R/P (HR: 5.486, 95% CI: 1.655-18.180), surgery + RT (HR: 0.125, 95% CI: 0.016-0.990) and WHO grade III (HR: 2.766, 95% CI: 1.146-6.676) were independently associated with cumulative survival. Lack of adhesion to and encasement of neurovascular structures was independently associated with R/P-free survival (HR: 2.002, 95% CI: 1.023-3.919). Conclusion: Surgical treatment was safe and effective for PCM. R/P, surgery + RT, and WHO grade III were independently associated with cumulative survival. Lack of adhesion to and encasement of neurovascular structures was independently associated with R/P-free survival. These factors should be paid attention to in surgical treatment of PCM.

18.
Exp Cell Res ; 357(1): 51-58, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28442265

RESUMO

Glioblastoma multiforme (GBM) is one of the most common brain malignancies worldwide and is typically associated with a dismal prognosis, yet the mechanisms underlying its aggressiveness remain unclear. Here, we revealed that ß-arrestin 1 was overexpressed in GBM and contributed to poorer outcome. Knockdown of ß-arrestin 1 suppressed the proliferation, invasiveness and glycolysis of GBM cells, and also enhanced temozolomide efficacy. Further, we discovered that knockdown of ß-arrestin 1 decreased the activity of Src, and suppression of Src signaling was critically involved in ß-arrestin 1 silencing-mediated suppression of GBM malignancies. Finally, we investigated the effect of ß-arrestin 1 knockdown on the tumor growth and survival of xenograft models, and found that shß-arrestin 1 apparently inhibited GBM growth in vivo and resulted in better survival of mice. Taken together, our findings suggest that knockdown of ß-arrestin 1 can suppress GBM cell proliferation, invasion and glycolysis by inhibiting Src signaling. Thus, targeting ß-arrestin 1 may be a potential therapeutic strategy for GBM treatment.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Transdução de Sinais , beta-Arrestina 1/metabolismo , Animais , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dacarbazina/análogos & derivados , Dacarbazina/farmacologia , Progressão da Doença , Regulação para Baixo/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Humanos , Camundongos , Invasividade Neoplásica/patologia , Proteínas Proto-Oncogênicas pp60(c-src)/metabolismo , Transdução de Sinais/efeitos dos fármacos , Temozolomida
20.
Oncotarget ; 7(34): 55555-55571, 2016 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-27487130

RESUMO

The overall survival remains undesirable in clinical glioma treatment. Inhibition of DNA-PKcs activity by its inhibitors suppresses tumor growth and enhances chemosensitivity of several tumors to chemotherapy. However, whether DNA-PKcs could be a potential target in glioma therapy remains unknown. In this study, we reported that the hyperactivated DNA-PKcs was profoundly correlated with glioma malignancy and observe a significant association between DNA-PKcs activation and survival of the glioma patients. Our data also found that inhibition of DNA-PKcs by its inhibitor KU0060648 sensitized glioma cells to TMZ in vitro. Specifically, we demonstrated that KU0060648 interrupted the formation of DNA-PKcs/AKT complex, leading to suppression of AKT signaling and resultantly enhanced TMZ efficacy. Combination of KU0060648 and TMZ substantially inhibited downstream effectors of AKT. The in vivo results were similar to those obtained in vitro. In conclusion, this study indicated that inhibition of DNA-PKcs activity could suppress glioma malignancies and increase TMZ efficacy, which was mainly through regulation of the of AKT signaling. Therefore, DNA-PKcs/AKT axis may be a promising target for improving current glioma therapy.


Assuntos
Antineoplásicos Alquilantes/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Proteína Quinase Ativada por DNA/antagonistas & inibidores , Dacarbazina/análogos & derivados , Glioma/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/irrigação sanguínea , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Dacarbazina/farmacologia , Dacarbazina/uso terapêutico , Sinergismo Farmacológico , Feminino , Glioma/irrigação sanguínea , Glioma/patologia , Humanos , Camundongos , Invasividade Neoplásica , Proteínas Proto-Oncogênicas c-akt/fisiologia , Temozolomida , Ensaios Antitumorais Modelo de Xenoenxerto
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