Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/genética , MicroARNs/genética , Femenino , Humanos , Masculino , Pronóstico , Rol , Sensibilidad y Especificidad , Análisis de SupervivenciaRESUMEN
The guanosine triphosphatase-activating protein RLIP76 is overexpressed in many malignant tumor cells, but it is unclear if RLIP76 overexpression contributes to the high proliferative potential of glioma cells. We demonstrate that RLIP76 messenger RNA and protein expression are positively correlated with glioma grade and that higher RLIP76 expression correlates with shorter patient survival. Immunohistochemical staining revealed that RLIP76 expression was positively correlated with the expression of Ki-67, a biomarker for cell proliferation. Inhibition of RLIP76 expression in U87 and U251 glioma cell lines by stable transfection of a targeted siRNA suppressed anchorage-independent growth and enhanced apoptosis in vitro. Conversely, overexpression of RLIP76 in SW1088 and U251 cell lines enhanced proliferation and reduced apoptosis. Inhibition of RLIP76 in U251 cells also significantly suppressed tumorigenicity and induced apoptosis in an endotopic xenograft mouse model. Moreover, we demonstrate that knockdown of RLIP76 increases apoptosis in different human gliomas independently of p53 status. In addition, a constitutively active Rac1 reversed both the suppression of proliferation and the promotion of apoptosis induced by the RLIP76-targeted siRNA, indicating that RLIP76 is an upstream activator of Rac1. Rac1-mediated suppression of apoptosis and promotion of proliferation were dependent on intact c-jun N-terminal kinase (JNK) signaling. Furthermore, we demonstrate that RLIP76 promotes proliferation and suppresses glioma cell apoptosis through a mechanism independent of Rho-selective GTPase-activating protein. Instead, we found that the adenosine triphosphatase function of Rlip76 modulates Rac1 activity by regulating Rac1 protein ubiquitylation and degradation. These data demonstrate that RLIP76 may suppress apoptosis and promote the proliferation of glioma cells by direct adenosine triphosphate-dependent xenobiotic transport and by activating the Rac1-JNK signaling pathway. Inhibition of RLIP76 signaling is a potential treatment for malignant glioma.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Proteínas Activadoras de GTPasa/metabolismo , Glioblastoma/metabolismo , Glioblastoma/patología , Sistema de Señalización de MAP Quinasas , Transportadoras de Casetes de Unión a ATP/genética , Animales , Apoptosis/genética , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidad , Línea Celular Tumoral , Proliferación Celular , Transformación Celular Neoplásica , Proteínas Activadoras de GTPasa/genética , Glioblastoma/genética , Glioblastoma/mortalidad , Células HEK293 , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Antígeno Ki-67/biosíntesis , Masculino , Ratones , Trasplante de Neoplasias , Pronóstico , Interferencia de ARN , ARN Mensajero/biosíntesis , ARN Interferente Pequeño , Ratas , Sobrevida , Trasplante Heterólogo , Proteína p53 Supresora de Tumor/biosíntesis , Ubiquitinación , Proteína de Unión al GTP rac1/biosíntesis , Proteína de Unión al GTP rac1/metabolismoRESUMEN
OBJECTIVE: To explore the clinical characteristics, diagnostic strategies and surgical techniques of hemangioblastoma (HB) in medulla oblongata. METHODS: The clinical and radiological characteristics, therapeutic processes and outcomes of 12 HB cases treated at our department from 2002 to 2012 were studied by retrospective analysis. RESULTS: Headache, somatic numbness and limb muscle weakness were the major symptoms of oblongata HB. Magnetic resonance imaging before surgery revealed a total of 12 single tumors. Among these tumors, upper (n = 1), middle (n = 7) and lower (n = 4) parts of medulla oblongata were involved. The locations were surface (n = 9) and intramedullary (n = 3). Three tumors had cyst. Digital subtraction angiography (DSA) was performed on 5 cases and it revealed that the main blood supply arteries of tumors were branches of posterior inferior cerebellar artery (PICA) and anterior inferior cerebellar artery (AICA).One case underwent pre-surgical embolism during angiography. Eleven tumors were totally resected and 1 was fulgurized.Symptoms improved (n = 8) and worsened (n = 2). And two patients died. All survivors were followed up for 3 months to 10 years and had a McCormick functional grading of I-II.One case relapsed 7 year later. CONCLUSION: For Cystic HB, small or medium sized substantial HB in middle and lower part of oblongata, surgical removal is often safe and symptoms may be lessened.It can be used as a first-line treatment. For large ( ≥ 3 cm) substantial HB or HB in upper part of oblongata, serious postoperative complications such as respiratory failure, neurogenic pulmonary edema or acute obstructive hydrocephalus may occur. Thus surgical resection should be prudently considered and possible consequences thoroughly discussed with the patients.
Asunto(s)
Neoplasias Encefálicas/cirugía , Hemangioblastoma/cirugía , Bulbo Raquídeo/patología , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
AIMS: Glioblastoma multiforme (GBM) is the deadliest glioma and its resistance to temozolomide (TMZ) remains intractable. Long non-coding RNAs (lncRNAs) play crucial roles in that and this study aimed to investigate underlying mechanism of HOXD-AS2-affected temozolomide sensitivity in glioblastoma. METHODS: We analyzed and validated the aberrant HOXD-AS2 expression in glioma specimens. Then we explored the function of HOXD-AS2 in vivo and in vitro and a clinical case was also reviewed to examine our findings. We further performed mechanistic experiments to investigate the mechanism of HOXD-AS2 in regulating TMZ sensitivity. RESULTS: Elevated HOXD-AS2 expression promoted progression and negatively correlated with prognosis of glioma; HOXD-AS2 attenuated temozolomide sensitivity in vitro and in vivo; The clinical case also showed that lower HOXD-AS2 sensitized glioblastoma to temozolomide; STAT3-induced HOXD-AS2 could interact with IGF2BP2 protein to form a complex and sequentially upregulate STAT3 signaling, thus forming a positive feedback loop regulating TMZ sensitivity in glioblastoma. CONCLUSION: Our study elucidated the crucial role of the HOXD-AS2-STAT3 positive feedback loop in regulating TMZ sensitivity, suggesting that this could be provided as a potential therapeutic candidate of glioblastoma.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , MicroARNs , Humanos , Temozolomida/farmacología , Temozolomida/uso terapéutico , Glioblastoma/genética , Retroalimentación , Resistencia a Antineoplásicos , Línea Celular Tumoral , Neoplasias Encefálicas/genética , MicroARNs/metabolismo , Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/uso terapéutico , Regulación Neoplásica de la Expresión Génica , Proteínas de Unión al ARN/metabolismo , Factor de Transcripción STAT3/metabolismoRESUMEN
GABA and enkephalin (ENK) are principle inhibitory transmitters in the rostral portion of the nucleus tractus solitarius (rNTS) for regulating the gustatory information. Although the existence of GABA- and ENK-immunoreactive (ir) profiles in the rNTS has been demonstrated, there are no morphological data revealing the connections between them. In the present study, using immunofluorescent and electron microscopic methods, we examined their relationship in the rNTS of rat. Results showed the following: (1) dense ENK-ir fibers and terminals and GABA-ir cell bodies, fibers, and terminals were observed in the rNTS; (2) ENK-ir terminals mainly make symmetric synapses with GABA-ir and immunonegative somas and dendrites; (3) co-existence of ENK/GABA-ir axon terminals and convergence of ENK- and GABA-ir terminals on one immunonegative soma or dendrite can also be observed. These results suggest that ENK should inhibit directly or excite indirectly (by blocking the inhibition of the GABAergic neurons) the gustatory neurons in the rNTS.
Asunto(s)
Encefalinas/metabolismo , Núcleo Solitario/metabolismo , Núcleo Solitario/ultraestructura , Ácido gamma-Aminobutírico/metabolismo , Animales , Axones/metabolismo , Axones/ultraestructura , Masculino , Microscopía Confocal , Microscopía Electrónica de Transmisión/métodos , Ratas , Ratas Sprague-Dawley , Sinapsis/metabolismo , Sinapsis/ultraestructuraRESUMEN
BACKGROUND: Dysautonomia after severe traumatic brain injury (TBI) is a clinical syndrome affecting a subgroup of survivors and is characterized by episodes of autonomic dysregulation and muscle overactivity. The purpose of this study was to determine the incidence of dysautonomia after severe TBI in an intensive care unit setting and analyze the risk factors for developing dysautonomia. METHODS: A consecutive series of 101 patients with severe TBI admitted in a major trauma hospital during a 2-year period were prospectively observed to determine the effects of age, sex, mode of injury, hypertension history, admission systolic blood pressure, fracture, lung injury, admission Glasgow Coma Scale (GCS) score, injury severity score, emergency craniotomy, sedation or analgesia, diffuse axonal injury (DAI), magnetic resonance imaging (MRI) scales, and hydrocephalus on the development of dysautonomia. Risk factors for dysautonomia were evaluated by using logistic regression analysis. RESULTS: Seventy-nine of the 101 patients met inclusion criteria, and dysautonomia was observed in 16 (20.3%) of these patients. Univariate analysis revealed significant correlations between the occurrence of dysautonomia and patient age, admission GCS score, DAI, MRI scales, and hydrocephalus. Sex, mode of injury, hypertension history, admission systolic blood pressure, fracture, lung injury, injury severity score, sedation or analgesia, and emergency craniotomy did not influence the development of dysautonomia. Multivariate logistic regression revealed that patient age and DAI were two independent predictors of dysautonomia. There was no independent association between dysautonomia and admission GCS score, MRI scales, or hydrocephalus. CONCLUSIONS: Dysautonomia frequently occurs in patients with severe TBI. A younger age and DAI could be risk factors for facilitating the development of dysautonomia.
Asunto(s)
Lesiones Encefálicas/complicaciones , Disautonomías Primarias/epidemiología , Adolescente , Adulto , Factores de Edad , Anciano , Lesiones Encefálicas/patología , Lesiones Encefálicas/fisiopatología , Niño , Estudios de Cohortes , Cuidados Críticos , Lesión Axonal Difusa/complicaciones , Lesión Axonal Difusa/epidemiología , Lesión Axonal Difusa/fisiopatología , Femenino , Humanos , Incidencia , Modelos Logísticos , Masculino , Persona de Mediana Edad , Disautonomías Primarias/diagnóstico , Disautonomías Primarias/terapia , Factores de Riesgo , Adulto JovenRESUMEN
Ventriculo-peritoneal (VP) shunt is the most common form of treatment for hydrocephalus and rejection to the shunt hardware is very rare. Also, in ventricul-atrial (VA) shunt thrombi and embolism are possible but rare complications. For the first time, we present a case of rejection and thrombosis following VP and VA shunt in the same patient.
Asunto(s)
Hidrocefalia/cirugía , Complicaciones Posoperatorias/cirugía , Derivación Ventriculoperitoneal/efectos adversos , Adolescente , Femenino , Cefalea/etiología , Humanos , Complicaciones Posoperatorias/etiología , Tercer Ventrículo/cirugía , Resultado del Tratamiento , Ventriculostomía/métodosRESUMEN
BACKGROUND: Multifocal glioblastoma is a rare type of glioblastoma with worse prognosis. In this article, we aimed to report two cases of classical multifocal glioblastoma. CASE PRESENTATION: In case 1, a 47-year-old male presented with dizziness, and once had a sudden loss of consciousness accompanied by convulsion of limbs. Contrast-enhanced MRI showed multiple lesions with heterogeneously ring-enhanced characters in the left hemisphere, diagnosed as multifocal glioblastoma. He underwent a craniotomy of all lesions, concurrent radiotherapy and chemotherapy as well as additional chemotherapy of temozolomide. After 2 cycles, repeat MRI showed that the new lesions already occurred and progressed. Eventually, he abandoned the chemotherapy after the 2 cycles and died 1 year later. In case 2, a 71-year-old male presented with a history of headache, left limb weakness, and numbness. Discontinuous convulsion of limbs once occurred. Contrast-enhanced MRI showed multiple lesions located in the right hemisphere, diagnosed as multifocal glioblastoma. He underwent a right frontoparietal craniotomy of the main lesion. Hemorrhage of the residual tumor and pulmonary artery embolism occurred synchronously. Eventually, his family decided not to pursue any further treatment and opted for hospice care and he passed away within 11 days of surgery. CONCLUSIONS: We reported two cases of typical multifocal glioblastoma. Valid diagnosis is crucial; then, resection of multiple lesions and canonical radio-chemotherapy probably bring survival benefits.
RESUMEN
Haemophilic pseudotumor is a rare complication of haemophilia occurring in 1-2% of patients and is more frequently located is in the long bones of the lower extremities and in the pelvis. We present the first case of an intracranial haemophilic pseudotumor in a patient with factor VIII deficiency.
Asunto(s)
Hematoma Subdural/etiología , Hemofilia A/complicaciones , Niño , Craneotomía , Epilepsia/etiología , Cefalea/etiología , Hematoma Subdural/diagnóstico por imagen , Hematoma Subdural/cirugía , Humanos , Imagen por Resonancia Magnética , Masculino , Hueso Parietal/patología , RadiografíaRESUMEN
OBJECTIVE: To compare the effects of treatment of spasmodic torticollis (ST) by neurovascular decompression, myotomy, and botulinum toxin type A and to investigate the mechanism of ST. METHODS: Nine ST patients who failed to respond to other conservative treatment methods underwent neurovascular decompression of accessory nerve. The effect of decompression was compared with that by botulinum toxin in 22 patients and that by myotomy in 13 patients. RESULTS: The symptoms and signs were improved to a certain degree by botulinum toxin treatment at first, but recurred and gradually worsened in several months. None of the 22 patients had reached a real cure by botulinum toxin type A treatment. Four of 13 patients undergoing myotomy improved a lot in the symptoms and 9 improved only a bit. However, weakness in neck movement was found in all patients after myotomy. Neurovascular decompression was performed on 9 patients, 5 of which had botulinum toxin treatment and 1 had undergone myotomy, and found that all of them had severe vascular compression in the accessory nerve. Obvious alleviation of symptoms was achieved 2 - 14 days after the operation in 8 patients, and 3 months later in 1 patient. All of the 9 patients resumed their nonenal work and life 6 months after the operation. No complication, such as nerve damage, infection, hemorrhage, leakage of cerebrospinal fluid, and weakness of neck, was found. CONCLUSIONS: Neurovascular compression may be the most important cause of ST. Microneurovascular decompression is effective for some patients. However, it is still difficult to judge its indication.
Asunto(s)
Toxinas Botulínicas Tipo A/uso terapéutico , Descompresión Quirúrgica , Tortícolis/tratamiento farmacológico , Tortícolis/cirugía , Adolescente , Adulto , Femenino , Humanos , Persona de Mediana Edad , Músculos del Cuello/cirugía , Pronóstico , Tortícolis/terapia , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: To investigate the microsurgical strategies of glioma located in lateral fissure area. METHODS: The clinical data of 123 patients with glioma located in lateral fissure area confirmed by pathology, 76 males and 47 females, aged 46.2 (4-75), were retrospectively analyzed. The optimal surgical approach and comprehensive therapeutic strategies were selected according to the imaging features and pathological properties of tumors. Resections were performed by the pterion approach in all cases to remove the tumors, navigational orientation was used in 17 cases, and supervision by B mode ultrasonography was used in 12 cases. The branches of middle cerebral artery and fissure vein were protected carefully. The patients with tumors above grade U, confirmed pathologically after resection, underwent chemotherapy ( teniposide + semustine or temozolomide) and radiotherapy that was designated individually according to the pathological grade and distribution of the tumors. Follow-up was conducted by telephone, mail or outpatient department visit on 102 of the 133 patients (82.9%). RESULTS: 82 patients (66.7%) underwent total resection, 18 (14.6%) underwent subtotal resection, 16 (13.0%) underwent major resection, and 7 (5.7%) underwent partial resection. Postoperatively cerebral vasospasm in 8 cases, brief aphasia and reaction clumsily in 4 cases, muscle strength decline in 3 cases, and epilepsy in 1 case, these patients were submitted to symptomatic treatment with progressive improvement of the above-mentioned signs and symptoms. One patient died of malignant intracranial hypertension. The follow-up showed that 97 patients survived over 1 year, the 5-year survival rate was 25.6%, and the average survival time was 21.7 months. CONCLUSION: The lateral fissure area glioma can be treated through proficient microsurgical technique after the anatomic training. It is the key in the surgery on the lateral fissure glioma to protect the main branches of middle cerebral artery, trunk of middle cerebral vein, and important brain functional areas.
Asunto(s)
Neoplasias Encefálicas/cirugía , Glioma/cirugía , Microcirugia/métodos , Procedimientos Neuroquirúrgicos/métodos , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: High-grade glioma (HGG) is a fatal human cancer. Bortezomib, a proteasome inhibitor, has been approved for the treatment of multiple myeloma but its use in glioma awaits further investigation. This study aimed to explore the chemotherapeutic effect and the underlying mechanism of bortezomib on gliomas. METHODS: U251 and U87 cell viability and proliferation were detected by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, tumor cell spheroid growth, and colony formation assay. Cell apoptosis and cell cycle were detected by flow cytometry. Temozolomide (TMZ)-insensitive cell lines were induced by long-term TMZ treatment, and cells with stem cell characteristics were enriched with stem cell culture medium. The mRNA levels of interested genes were measured via reverse transcription-quantitative polymerase chain reaction, and protein levels were determined via Western blotting/immunofluorescent staining in cell lines and immunohistochemical staining in paraffin-embedded sections. Via inoculating U87 cells subcutaneously, glioma xenograft models in nude mice were established for drug experiments. Patient survival data were analyzed using the Kaplan-Meier method. RESULTS: Bortezomib inhibited the viability and proliferation of U251 and U87 cells in a dose- and time-dependent manner by inducing apoptosis and cell cycle arrest. Bortezomib also significantly inhibited the spheroid growth, colony formation, and stem-like cell proliferation of U251 and U87 cells. When administrated in combination, bortezomib showed synergistic effect with TMZ in vitro and sensitized glioma to TMZ treatment both in vitro and in vivo. Bortezomib reduced both the mRNA and protein levels of Forkhead Box M1 (FOXM1) and its target gene Survivin. The FOXM1-Survivin axis was markedly up-regulated in established TMZ-insensitive glioma cell lines and HGG patients. Expression levels of FOXM1 and Survivin were positively correlated with each other and both related to poor prognosis in glioma patients. CONCLUSIONS: Bortezomib was found to inhibit glioma growth and improved TMZ chemotherapy efficacy, probably via down-regulating the FOXM1-Survivin axis. Bortezomib might be a promising agent for treating malignant glioma, alone or in combination with TMZ.
Asunto(s)
Antineoplásicos/uso terapéutico , Bortezomib/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Proteína Forkhead Box M1/genética , Glioma/tratamiento farmacológico , Survivin/genética , Temozolomida/uso terapéutico , Adolescente , Adulto , Anciano , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Bortezomib/farmacología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Femenino , Proteína Forkhead Box M1/metabolismo , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Glioma/genética , Glioma/metabolismo , Humanos , Masculino , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Survivin/metabolismo , Temozolomida/farmacología , Adulto JovenRESUMEN
UbcH10 is one of the key regulators of cell cycle progression through the mitotic spindle assembly checkpoint pathway. Recently, aberrantly high UbcH10 expression has been demonstrated in a variety of malignancies. However, its role in astrocytic carcinogenesis is not well defined. This study investigated the splice pattern of the UbcH10 gene and its expression status in astrocytomas of different grades. Consequently, UbcH10 splice variant 1 (GenBank accession nos. NM_007019) was detected in astrocytomas and normal brain tissues by RT-PCR and sequence analysis. Expression levels of UbcH10 mRNA were elevated in high- versus low-grade astrocytomas (64.33+/-60.98 vs 8.36+/-8.15, respectively; p=0.000) or normal controls (64.33+/-60.98 vs 1.00+/-1.57, respectively; p=0.000), as determined by quantitative real time PCR analysis. Similarly, immunohistochemistry study showed increased UbcH10 labelling index in high-grade astrocytomas versus low-grade tumors (10.53+/-5.79% vs 4.23+/-2.85%, respectively; p=0.000) or normal controls (10.53+/-5.79% vs 0.0+/-0.0%, respectively; p=0.000) and, a positive correlation between UbcH10 immunoreactivity and Ki-67 immunostaining was also noted (Spearman r=0.63, p<0.001). These data suggest that overexpression of UbcH10 may serve as one important molecular mechanism that underlies the astrocytic carcinogenesis.
Asunto(s)
Astrocitoma/enzimología , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/enzimología , Enzimas Ubiquitina-Conjugadoras/genética , Enzimas Ubiquitina-Conjugadoras/metabolismo , Empalme Alternativo/genética , Astrocitos/enzimología , Astrocitos/patología , Astrocitoma/diagnóstico , Astrocitoma/fisiopatología , Biomarcadores de Tumor/análisis , Encéfalo/enzimología , Encéfalo/patología , Encéfalo/fisiopatología , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/fisiopatología , Regulación Enzimológica de la Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Inmunohistoquímica , Isoenzimas/genética , Isoenzimas/metabolismo , Antígeno Ki-67/metabolismo , Pronóstico , ARN Mensajero/análisis , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Ubiquitina/metabolismo , Regulación hacia Arriba/genéticaRESUMEN
BACKGROUND: This study was conducted to evaluate the effect of 3D-RA on the treatment of SCVMs. METHODS: Twelve patients with SCVM were retrospectively reviewed for details of 2D and 3D-RA findings. Pretherapeutic 2D and 3D-RA angiograms were compared with respect to 4 critical categories of parameters: (1) the exact anatomic location, size, and extent; (2) the definitive diagnosis; (3) the precise angioarchitectural configuration; and (4) the contribution to further intervention. RESULTS: Overall, 2D and 3D-RA were equally effective in demonstrating the exact anatomic location, size, and extent, and establishing the definitive diagnosis of SCVM in all 12 cases. 3-Dimensional rotational angiography demonstrated precise angioarchitectural configuration in 8 (8/12) cases, facilitated treatment in 6 (6/12) cases, and modified therapeutic strategies in 2 (2/12) cases via information not available from 2D-DSA images. Both 2D and 3D-RA contributed equally to the therapeutic intervention in 4 (4/12) patients. No complications occurred as a result of 3D-RA. CONCLUSIONS: 3-Dimensional rotational angiography may enhance our ability to treat SCVMs with complex angioarchitecture and is an ideal addition to conventional 2D angiography in the management of these vascular lesions.
Asunto(s)
Angiografía de Substracción Digital , Malformaciones Vasculares del Sistema Nervioso Central/diagnóstico por imagen , Malformaciones Vasculares del Sistema Nervioso Central/cirugía , Imagenología Tridimensional , Enfermedades Vasculares de la Médula Espinal/diagnóstico por imagen , Enfermedades Vasculares de la Médula Espinal/cirugía , Adolescente , Adulto , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reproducibilidad de los Resultados , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVE: Cytoplasmic polyadenylation element binding protein 4 (CPEB4) is a regulator of gene expression at transcriptional level and has been reported to be associated with biological malignancy in cancers. However, little was known about the correlation between CPEB4 and glioblastoma cell proliferation and the prognostic significance in patients. Our aim was to investigate the functional role and prognostic value of CPEB4 in glioblastoma. PATIENTS AND METHODS: We determined the expression of CPEB4 protein using immunohistochemistry in tissue microarrays containing 278 glioma patients (including 98 primary glioblastomas) and evaluated its association with pathological grades and clinical outcome by univariate and multivariate analyses. And then, lentiviral-mediated RNAi targeting CPEB4 was utilized to study the role of CPEB4 in glioblastoma cell proliferation. RESULTS: In our cohort, CPEB4 expression was positively related to glioma pathological grade (pâ¯<â¯0.01) and elevated in glioblastoma (pâ¯<â¯0.01). High expression of CPEB4 was associated with significantly poor prognosis, and could be identified as an independent risk factor for overall survival (OS) and progression-free survival (PFS) of glioblastoma patients (hazard ratio (HR)â¯=â¯1.730, pâ¯=â¯0.014 and HRâ¯=â¯1.877, pâ¯=â¯0.004, respectively). In vitro studies further showed that downregulation of CPEB4 significantly reduced the growth rate of T98G and U251 cells comparing with the controls. CONCLUSION: Our study indicated that increased expression of CPEB4 in primary glioblastoma is a novel biomarker for predicting poor outcome of patients and suppression of CPEB4 inhibit tumor cell proliferation, suggesting a potential therapeutic target for glioblastoma.
Asunto(s)
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/metabolismo , Proliferación Celular/fisiología , Glioblastoma/diagnóstico , Glioblastoma/metabolismo , Proteínas de Unión al ARN/biosíntesis , Anciano , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/genética , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Glioblastoma/genética , Células HEK293 , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Proteínas de Unión al ARN/genética , Tasa de Supervivencia/tendencias , Resultado del TratamientoRESUMEN
OBJECTIVE: The aim of the present study is to investigate the expression profiles of circular RNAs (circRNAs) in IDH-wild type (IDH-wt) glioblastoma and explore the differences in circRNAs expression between IDH-wt glioblastoma and adjacent normal brain. PATIENTS AND METHODS: circRNA expression profiles were detected by circRNA microarray in three matched pairs of IDH-wt glioblastoma and adjacent normal brain. qRT-PCR was used to verify the differential expression of circRNAs from microarray analysis. Bioinformatics analysis was used to analyze potential functions of the differentially expressed circRNAs in IDH-wt glioblastoma. RESULTS: Compared with the adjacent normal brain tissues, 254 circRNAs were upregulated and 361 circRNAs were downregulated in IDH-wt glioblastoma with a ≥1.5-fold change. A total of 12 differentially expressed circRNAs were randomly selected and validated a good correlation of results from circRNA-seq with qRT-PCR. Gene Ontology (GO) analysis revealed the differentially expressed circRNAs possibly involved in cell division, DNA damage repair, cytoskeleton, and protein ubiquitination. 46 and 50 miRNAs were predicted to be adsorbed by the top 10 upregulated circRNAs and top 10 downregulated circRNAs, respectively. CONCLUSION: Differential expression of circRNAs may be associated with IDH-wt glioblastoma development and progression, and these circRNAs can be identified as biomarkers for prognosis prediction and targets for treatment.
Asunto(s)
Biomarcadores/sangre , Glioblastoma/genética , MicroARNs/sangre , ARN/sangre , Anciano , Biología Computacional/métodos , Regulación hacia Abajo , Humanos , Masculino , MicroARNs/genética , Persona de Mediana Edad , ARN Circular , ARN Mensajero/metabolismo , Regulación hacia ArribaRESUMEN
Glioma is the most aggressive and malignant primary brain tumor in adults. In the present study, we identified a vital oncoprotein, capping actin protein, gelsolin-like (CapG), and investigated its roles in the prognosis, proliferation and metastasis in glioma. The mRNA and protein levels of CapG were significantly increased in human glioma, and higher CapG expression was an independent prognostic factor for predicting unfavorable prognosis. The expression level of CapG was found to be associated with several common molecular features of glioblastoma (GBM; WHO grade IV glioma) in The Cancer Genome Atlas (TCGA) cohort. When analyzing the prognosis of GBM patients according to these molecular features, we observed that the prognostic value of CapG was affected by amplification of CDK6 or EGFR. However, overexpression of CapG markedly promoted cell growth in vitro, while depletion of CapG significantly inhibited cell proliferation by blocking the cell cycle in G1/S transition. Moreover, CapG manipulation in glioma cell lines U87 and U251 showed CapG-dependent cellular migration and invasiveness. These data suggest that CapG may serve as a prognostic biomarker with potentially important therapeutic implications for glioma.
Asunto(s)
Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Proteínas de Microfilamentos/metabolismo , Proteínas Nucleares/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/secundario , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Puntos de Control de la Fase G1 del Ciclo Celular , Expresión Génica , Glioma/mortalidad , Glioma/patología , Glioma/secundario , Humanos , Proteínas de Microfilamentos/biosíntesis , Proteínas de Microfilamentos/genética , Invasividad Neoplásica , Proteínas Nucleares/biosíntesis , Proteínas Nucleares/genética , PronósticoRESUMEN
OBJECTIVE: G-protein-coupled receptors 65 (GPR65), identified as an acid-sensing receptor, is overexpressed in several malignancies and promote tumor development. Our aim was to investigate the expression and prognostic value of GPR65 in glioblastoma. MATERIALS AND METHODS: We determined the expression of GPR65 protein using immunohistochemistry in tissue microarrays containing 11 Grade I, 107 Grade II, 47 Grade III, and 102 Grade IV gliomas and 16 normal brains. Then we evaluated its association with pathological grades, prognosis, and recurrence. The Cancer Genome Atlas (TCGA) group (N=528) was further employed to examine transcriptional level of GPR65 in glioblastoma and the correlation between GPR65 expression and clinical outcome. RESULTS: In our cohort, GPR65 expression was positively related to glioma pathological grade (p<0.01) and elevated in glioblastoma (p<0.01). High expression of GPR65 was associated with significantly short overall survival (OS) (p=0.013) and progression-free survival (PFS) (p=0.029), and could be identified as an independent risk factor for OS of glioblastoma patients (Hazard Ratio [HR]=1.596, p=0.037). As an aiding evidence, increased GPR65 mRNA expression was also found in TCGA glioblastoma group (p<0.001) and its high level predicted a poor clinical outcome (OS, p=0.003; PFS, p=0.001). CONCLUSION: Our findings suggest that GPR65 is overexpressed in glioblastoma and its high expression predicts unfavorable clinical outcome for patients. Targeting GPR65 may serve as a potential therapy for treating glioblastoma.
Asunto(s)
Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Regulación Neoplásica de la Expresión Génica , Glioblastoma/genética , Glioblastoma/patología , Receptores Acoplados a Proteínas G/genética , Adulto , Neoplasias Encefálicas/metabolismo , Estudios de Cohortes , Bases de Datos Genéticas/tendencias , Femenino , Glioblastoma/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Receptores Acoplados a Proteínas G/biosíntesisRESUMEN
OBJECTIVE: To clone and identify expression pattern of the novel LNX gene, and characterize its molecular mechanism in all grades of human gliomas. METHODS: From a fetal brain cDNA library, we isolated the novel human LNX gene. The expression pattern of LNX gene in 16 normal tissues was examined by MTC panel (Clontech). Microarray were adopted and hybridized with LNX probes to examine the expression of novel gene in gliomas. Northern hybridization was used for verifying expression of LNX gene in gliomas. Two-hybrid screen in yeast was used to identify human LNX interacting proteins. Pull-down assays and Co-immunoprecipitation were transfected in HEK293 cells according to the lipofectAMINE protocol. RESULTS: We isolated a 3.7 kb cDNA containing an open reading frame (ORF) of 1,899 bp and a putative 632 amino acids protein, which was located on 4q12. cDNA microarray showed LNX was down-regulated in all 18 glioma samples and it was testified by Northern-blot. The MTC panel showed a ubiquitous expression pattern which highly expressed in adult brain, kidney and pancreas, while weak expression in heart, lung, etc. The two-hybrid screen in yeast revealed that LNX interacted with SKIP (Ski interacting protein) via PDZ domains. The co-immunoprecipation suggested that LNX interacted with SKIP in HEK293 cells and could affect the subcellular localization of Numb, which indicated that LNX might function as a molecular anchor that localized Numb to the subcellular site of its interaction with Notch. CONCLUSION: cDNA microarray technology is a powerful technique in screening and locking differentially expressed genes in gliomas, LNX was closely related to human gliomas and suggested playing an important role in gliomas by notch signal approach.
Asunto(s)
Glioma/genética , Ubiquitina-Proteína Ligasas/genética , Clonación Molecular , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunoprecipitación , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
BACKGROUND: The radiochemotherapy regimen concomitantly employing temozolomide (TMZ) chemotherapy and radiotherapy (RT) 4 weeks after surgery, followed by 6 cycles of TMZ is a common treatment for glioblastoma (GBM). However, its median overall survival (OS) is only 14.6 months. This study was to explore the effectiveness and safety of early TMZ chemotherapy between surgery and chemoradiotherapy plus the standard concomitant radiochemotherapy regimen. METHODS: A randomized, parallel group, open-label study of 99 newly diagnosed GBM patients was conducted at 10 independent Chinese neurosurgical departments from June 2008 to June 2012. Patients were treated with concomitant radiochemotherapy regimen plus early postsurgical temozolomide (early TMZ group) or standard concomitant radiochemotherapy regimen (control group). Overall response was assessed based on objective tumor assessments, administration of corticosteroid and neurological status test. Hematological, biochemical, laboratory, adverse event (AE), and neurological condition were measured for 24 months of follow-up. The primary efficacy endpoint of this study was overall survival (OS). The secondary endpoint was progression free survival (PFS). RESULTS: The median OS time in the early TMZ group was 17.6 months, compared with 13.2 months in the control group (log-rank test P = 0.021). In addition, the OS rate in the early TMZ group was higher at 6, 12, and 18 months than in the control group, respectively (P < 0.05). The median PFS time was 8.7 months in the early TMZ group and 10.4 months in the control group (log-rank test P = 0.695). AEs occurred in 29 (55.8%) and 31(73.8%) patients respectively in early and control groups, including nausea (15.4% vs. 33.3%), vomiting (7.7% vs. 28.6%), fever (7.7% vs. 11.9%), and headache (3.8% vs. 23.8%). Only 30.8% and 33.3% were drug-related, respectively. CONCLUSIONS: Addition of TMZ chemotherapy in the early break of the standard concomitant radiochemotherapy regimen was well tolerated and significantly improved the OS of the GBM patients, compared with standard concomitant radiochemotherapy regimen. However, a larger randomized trial is warranted to verify these results.