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BACKGROUND: Glioblastoma is the most common and most aggressive type of primary brain tumor. OBJECTIVE: The aim of this study was to investigate the efficacy and safety of intranasal granulocyte-macrophage colony stimulating factor (GM-CSF) administration combined with chemoradiotherapy in patients with glioblastoma who underwent surgery. METHODS: Ninety-two patients were randomly divided into two groups: a control group (n= 46), who received radiotherapy with adjuvant local delivery of nimustine hydrochloride (ACNU) and systemic administration of temozolomide, and an intervention group (n= 46), who received intranasal GM-CSF prior to each cycle of adjuvant chemotherapy in addition to the treatment of the control group. Karnofsky performance status (KPS) scores, progression-free survival (PFS), overall survival (OS), and adverse effects were calculated and compared between the two groups. RESULTS: Compared with the control group, the intervention group had longer PFS (7.8 vs. 6.9 months, P= 0.016) and OS (19.2 vs. 17.1 months, P= 0.045, without adjustment for interim analyses). The KPS scores were also higher in the intervention group than in the control group after 6 months (84.35 ± 8.86 vs. 80.65 ± 7.72; t= 4.552, P= 0.036). Furthermore, the patients in the intervention group had lower incidence of neutropenia and thrombocytopenia (8.7% vs. 29.5%, P= 0.012; 8.7% vs. 18.2%, P= 0.186). Other adverse events were similar in both groups, and most adverse events were grade I/II and resolved spontaneously. CONCLUSION: Intranasal GM-CSF enhances the efficacy of the local ACNU administration combined with oral temozolomide chemotherapy. The survival and performance status were significantly improved in patients with glioblastoma after surgery. Additionally, the GM-CSF therapy was able to reduce the occurrence of chemotherapy-related neutropenia and thrombocytopenia.
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Neoplasias Encefálicas , Glioblastoma , Neutropenia , Trombocitopenia , Humanos , Temozolomida/uso terapéutico , Glioblastoma/tratamiento farmacológico , Glioblastoma/radioterapia , Nimustina/uso terapéutico , Factor Estimulante de Colonias de Macrófagos/uso terapéutico , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Neutropenia/tratamiento farmacológico , Trombocitopenia/tratamiento farmacológico , Granulocitos , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/radioterapiaRESUMEN
Malignant gliomas are aggressive primary neoplasms that originate in the glial cells of the brain or the spine with notable resistance to standard treatment options. We carried out the study with the aim to shed light on the sensitization of resveratrol to temozolomide (TMZ) against glioma through the Wnt signaling pathway. Initially, glioma cell lines with strong resistance to TMZ were selected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Then, the glioma cells were subjected to resveratrol, TMZ, Wnt signaling pathway inhibitors, and activators. Cell survival rate and inhibitory concentration at half maximum value were detected by MTT, apoptosis by flow cytometry, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining, in vitro proliferation by hanging drop method and ß-catenin translocation into nuclei by TOP/FOP-FLASH assay. The expressions of the Wnt signaling pathway-related and apoptosis-related factors were determined by western blot analysis. Nude mice with glioma xenograft were established to detect tumorigenic ability. Glioma cell lines T98G and U138 which were highly resistant to TMZ were selected for subsequent experiments. Resveratrol increased the efficacy of TMZ by restraining cell proliferation, tumor growth, and promoting cell apoptosis in glioma cells. Resveratrol inhibited Wnt2 and ß-catenin expressions yet elevated GSK-3ß expression. Moreover, the Wnt signaling pathway participates in the sensitivity enhancing of resveratrol to TMZ via regulating O 6 -methylguanine-DNA methyltransferase (MGMT) expression. Resveratrol sensitized TMZ-induced glioma cell apoptosis by repressing the activation of the Wnt signaling pathway and downregulating MGMT expression, which may confer new thoughts to the chemotherapy of glioma.
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Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Resveratrol/farmacología , Temozolomida/farmacología , Vía de Señalización Wnt/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Neoplasias Encefálicas/metabolismo , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioma/metabolismo , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Humanos , Ratones , Ratones Desnudos , O(6)-Metilguanina-ADN Metiltransferasa/metabolismoRESUMEN
As the most common and lethal of intracranial tumors, glioma accounts for 81% of all malignant brain tumors. Research data have identified the role of microRNAs (miRs) as functional suppressors in the progression of Glioma. The present study aimed to, ascertain as to whether microRNA-499a (miR-499a) influences cell proliferation and apoptosis through the MAPK signaling pathway by targeting Notch1 in glioma. Both glioma and adjacent tissues between 2012-2016, were obtained from People's Hospital of Zhengzhou University (Henan Provincial People's Hospital). The collected glioma cells were treated with miR-449a mimic, miR-449a inhibitor, siRNA-Notch1, or SB230580 (an inhibitor of the MAPK signaling pathway). Verification of the targeting effect of miR-449a on Notch1 was provided by a dual-luciferase reporter gene assay. The expressions of miR-449a, Notch1, p38 mitogen-activated protein kinase (p38MAPK), extracellular regulated protein kinases (ERK1/2), B-cell lymphoma-2 (Bcl-2), Bcl-2 associated X protein (bax), CyclinD1, and phosphorylation of p38MAPK (p-p38MAPK) and ERK1/2 (p-ERK1/2) in tissues and cells were detected by means of reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analysis methods. Cellular processes of proliferation, cell cycle and apoptosis were evaluated by MTT and BrdU assays as well as flow cytometry, respectively. Notch1 was subsequently identified to be a target gene of miR-499a. After the cells were treated with miR-449a mimic, siRNA-Notch1 or SB230580, decreased expressions of Notch1, Bcl-2, CyclinD1, ERK1/2 and p-ERK1/2, cell proliferation as well as cells arrested at the S stage with elevated expressions levels of p38MAPK, p-p38MAPK, Bax, as well as increased cell apoptosis and number of cells arrested in G0/G1 stage were assessed. Taken together, based on the evidence obtained from the present study, assertions were subsequently made suggesting that MiR-499a targeted-inhibition of Notch1 may be a promising future therapeutic strategy for glioma treatment, by means of overexpressing of miR-499a resulting in the inhibition of glioma cell proliferation and promotion of cell apoptosis through suppression of the MAPK signaling pathway by decreasing Notch1.
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Apoptosis/fisiología , Neoplasias Encefálicas/metabolismo , Proliferación Celular/fisiología , Glioma/metabolismo , MicroARNs/metabolismo , Adolescente , Adulto , Anciano , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/cirugía , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/cirugía , Línea Celular Tumoral , Niño , Femenino , Regulación Neoplásica de la Expresión Génica , Glioma/patología , Glioma/cirugía , Humanos , Sistema de Señalización de MAP Quinasas/fisiología , Masculino , Persona de Mediana Edad , Receptor Notch1/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Glioblastoma (GBM) is one of the worst cancers with bad prognosis despite systemic chemotherapy and radiotherapy after surgery. METHODS: In this study, 71 patients with GBM were enrolled and randomly assigned to two groups: Receiving radiotherapy with concomitant and adjuvant temozolomide (TMZ) (TMZ, standard therapy) after surgery, or receiving radiotherapy with concomitant and adjuvant local delivery of nimustine (ACNU) rendezvousing with oral TMZ (rendezvous therapy). In the follow-up of all patients and the progression-free survival (PFS), overall survival (OS), Karnofsky performance score (KPS) and toxicities were recorded. RESULTS: For the whole cohort, the median OS was 18.0 months, and the median PFS was 7.8 months. A significantly longer OS was observed in patients received rendezvous therapy than those who receiving standard therapy (18.5 months vs. 16.0 months; P = 0.014), as well as PFS (8.8 months vs. 7.0 months; P = 0.008). The KPS ≥70 rates were 81.8%, 40.9%, 20.5% in 1, 2, and 3 years for the rendezvous therapy group, significantly superior to standard therapy group. The most common toxicities were tolerable gastrointestinal reaction, liver dysfunction, and hematological toxicities, which were relieved with symptomatic treatment. Grade 3 or 4 toxicity was documented in 8 (18.3%) patients in rendezvous therapy group, while it was observed in 6 (22.2%) patients in standard therapy group during whole treatment process. CONCLUSIONS: Compared to standard therapy, the antitumor effects of rendezvous therapy were more effective in GBM patients without increasing the toxicities.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Glioblastoma/tratamiento farmacológico , Glioblastoma/radioterapia , Radioterapia , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quimioradioterapia , Terapia Combinada , Dacarbazina/administración & dosificación , Dacarbazina/análogos & derivados , Femenino , Estudios de Seguimiento , Glioblastoma/diagnóstico , Glioblastoma/mortalidad , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Nimustina/administración & dosificación , Modelos de Riesgos Proporcionales , Calidad de Vida , Radioterapia/efectos adversos , Radioterapia/métodos , Temozolomida , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
This study aims to explore the role of long noncoding RNA (lncRNA)-HOX transcript antisense intergenic RNA (HOTAIR) in the occurrence and progression of glioma. Fresh glioma and normal brain tissues were classified into a glioma group (n = 67) and a normal group (n = 64) respectively. U87 cells were assigned into the blank, sh-NC, and sh-HOTAIR groups. Quantitative real-time polymerase chain reaction (qRT-PCR) was utilized to determine HOTAIR expression. Cell proliferation, cell cycle and cell apoptosis rates were detected by cell counting kit-8 (CCK-8) and flow cytometry (FCM). Scratch test and transwell assay were conducted for cell migration and invasion. Orthotopic glioma tumor model in nude mice was established by inoculating tumor cell suspension. Hematoxylin-Eosin (HE) staining was used to observe the growth and invasion of orthotopic glioma tumors. The expression of HOTAIR and cell viability was found to be lowest in the sh-HOTAIR group among the three groups. The sh-HOTAIR group exhibited a higher apoptotic rate and lower number of cell migration compared with the blank and sh-NC groups. Additionally, the speed of wound healing was slower, the migration distance decreased and the survival time of nude mice was extended in the sh-HOTAIR compared to the other groups. Moreover, the sh-HOTAIR group demonstrated reduced lesion sizes and inflammation, no convulsions or hemiplegia and lesser number of satellite metastases. Our findings support that down-regulation of HOTAIR could inhibit cell proliferation, promote cell apoptosis as well as suppress cell invasion and migration in the progression of glioma.
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Neoplasias Encefálicas/genética , Regulación hacia Abajo , Glioma/genética , ARN Largo no Codificante/genética , Animales , Apoptosis , Línea Celular Tumoral , Movimiento Celular , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Trasplante de NeoplasiasRESUMEN
As there are multiple factors causing hydrocephalus subsequent to intraventricular hemorrhage (IVH), it is difficult to achieve the best treatment effect using a single drug alone. In the present study, the protective effect of combination treatment with granulocyte-colony stimulating factor (G-CSF) and lithium chloride against hydrocephalus after IVH was investigated. A total of 130 adult male Sprague-Dawley rats were divided into five groups, including the IVH control, G-CSF treatment, lithium chloride treatment, combination treatment and sham surgery groups. An IVH rat model was established in order to examine the effect of combination treatment on hydrocephalus incidence. A TUNEL assay was performed to detect neuronal apoptosis in the five groups. In addition, the protein expression levels of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) were detected by western blot analysis. The differentiation of nerve cells in the brain tissue obtained from the five rat groups was also determined with double immunofluorescence staining. The results demonstrated that administration of G-CSF or lithium chloride alone was able to only partly relieve the incidence of hydrocephalus after IVH. By contrast, combination treatment with G-CSF and lithium chloride significantly attenuated the development of hydrocephalus following IVH. TUNEL assay showed that neuronal apoptosis was significantly reduced by the combination treatment with G-CSF and lithium chloride. Furthermore, the expression of Bcl-2 was upregulated, whereas Bax expression was downregulated in the combination treatment group. The results also detected the highest expression of BrdU/GFAP, BrdU/NeuN and BrdU/PSA-NCAM in the combination treatment group. In conclusion, the combination of endogenous neural stem cell mobilization (using G-CSF) and lithium chloride treatment resulted in highly reduced incidence of hydrocephalus after IVH by inhibiting neuronal apoptosis.
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OBJECTIVE: To determine the effect of the angiogenesis inhibitor Cilengitide (EMD 121974) on glioblastoma growth and associated angiogenesis in the brains of nude mice. METHODS: Human glioblastoma cells (10 U87MG cells) in 1 mul of medium were stereotactically injected during a 20-minute period into the caudate/putamen of nude mice. The mice were intraperitoneally treated daily with Cilengitide or solvent (control) beginning 5 days after tumor injection. The mice were sacrificed from 1 hour to 63 days after tumor implantation and examined for tumor size, vascularity, apoptosis, and cell replication. RESULTS: This injection technique resulted in a highly reproducible, localized, spherical tumor cell placement in the parenchyma without reflux into the subarachnoid space or penetration into the ventricle. Serial brain sections showed the tumor size remained unchanged at 1 to 2 mm for approximately 30 to 40 days. Thereafter, the control tumors showed exponential growth to a volume of 120 mm, with death of the mice at approximately 8 to 9 weeks. Serial staining for Ki-67, a marker for cell replication, and CD31, an indicator for angiogenesis, demonstrated an increase in proportion to the growth of the tumor. In contrast, the tumor volume in Cilengitide-treated mice stayed unchanged at 1 to 2 mm during the entire length of the experiment, with staining for Ki-67 and CD31 remaining low. CONCLUSION: This standardized brain tumor model is highly reproducible and useful for testing new treatment regimens. Cilengitide is highly effective in suppressing blood vessel growth, thereby controlling orthotopic growth of this glioblastoma cell line.