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1.
Nat Rev Dis Primers ; 10(1): 33, 2024 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-38724526

RESUMEN

Gliomas are primary brain tumours that are thought to develop from neural stem or progenitor cells that carry tumour-initiating genetic alterations. Based on microscopic appearance and molecular characteristics, they are classified according to the WHO classification of central nervous system (CNS) tumours and graded into CNS WHO grades 1-4 from a low to high grade of malignancy. Diffusely infiltrating gliomas in adults comprise three tumour types with distinct natural course of disease, response to treatment and outcome: isocitrate dehydrogenase (IDH)-mutant and 1p/19q-codeleted oligodendrogliomas with the best prognosis; IDH-mutant astrocytomas with intermediate outcome; and IDH-wild-type glioblastomas with poor prognosis. Pilocytic astrocytoma is the most common glioma in children and is characterized by circumscribed growth, frequent BRAF alterations and favourable prognosis. Diffuse gliomas in children are divided into clinically indolent low-grade tumours and high-grade tumours with aggressive behaviour, with histone 3 K27-altered diffuse midline glioma being the leading cause of glioma-related death in children. Ependymal tumours are subdivided into biologically and prognostically distinct types on the basis of histology, molecular biomarkers and location. Although surgery, radiotherapy and alkylating agent chemotherapy are the mainstay of glioma treatment, individually tailored strategies based on tumour-intrinsic dominant signalling pathways have improved outcome in subsets of patients.


Asunto(s)
Neoplasias Encefálicas , Glioma , Humanos , Glioma/genética , Glioma/fisiopatología , Glioma/terapia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/fisiopatología , Pronóstico , Niño , Isocitrato Deshidrogenasa/genética , Mutación
2.
Nat Rev Dis Primers ; 10(1): 34, 2024 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-38724549
3.
Clin Neurophysiol ; 161: 256-267, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38521679

RESUMEN

OBJECTIVE: We investigated the feasibility of recording cortico-cortical evoked potentials (CCEPs) in patients with low- and high-grade glioma. We compared CCEPs during awake and asleep surgery, as well as those stimulated from the functional Broca area and recorded from the functional Wernicke area (BtW), and vice versa (WtB). We also analyzed CCEP properties according to tumor location, histopathology, and aphasia. METHODS: We included 20 patients who underwent minimally invasive surgery in an asleep-awake-asleep setting. Strip electrode placement was guided by classical Penfield stimulation of positive language sites and fiber tracking of the arcuate fascicle. CCEPs were elicited with alternating monophasic single pulses of 1.1 Hz frequency and recorded as averaged signals. Intraoperatively, there was no post-processing of the signal. RESULTS: Ninety-seven CCEPs from 19 patients were analyzed. There was no significant difference in CCEP properties when comparing awake versus asleep, nor BtW versus WtB. CCEP amplitude and latency were affected by tumor location and histopathology. CCEP features after tumor resection correlated with short- and long-term postoperative aphasia. CONCLUSION: CCEP recordings are feasible during minimally invasive surgery. CCEPs might be surrogate markers for altered connectivity of the language tracts. SIGNIFICANCE: This study may guide the incorporation of CCEPs into intraoperative neurophysiological monitoring.


Asunto(s)
Neoplasias Encefálicas , Potenciales Evocados , Glioma , Lenguaje , Procedimientos Quirúrgicos Mínimamente Invasivos , Humanos , Glioma/cirugía , Glioma/fisiopatología , Masculino , Femenino , Neoplasias Encefálicas/cirugía , Neoplasias Encefálicas/fisiopatología , Persona de Mediana Edad , Adulto , Anciano , Potenciales Evocados/fisiología , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Estimulación Eléctrica/métodos , Monitorización Neurofisiológica Intraoperatoria/métodos , Corteza Cerebral/fisiopatología , Corteza Cerebral/cirugía , Vigilia/fisiología
5.
Neuropsychologia ; 198: 108876, 2024 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-38555064

RESUMEN

We retrospectively analyzed data from 15 patients, with a normal pre-operative cognitive performance, undergoing awake surgery for left fronto-temporal low-grade glioma. We combined a pre-surgical measure (fMRI maps of motor- and language-related centers) with intra-surgical measures (MNI-registered cortical sites data obtained during intra-operative direct electrical stimulation, DES, while they performed the two most common language tasks: number counting and picture naming). Selective DES effects along the precentral gyrus/inferior frontal gyrus (and/or the connected speech articulation network) were obtained. DES of the precentral gyrus evoked the motor speech arrest, i.e., anarthria (with apparent mentalis muscle movements). We calculated the number of shared voxels between the lip-tongue and overt counting related- and silent naming-related fMRI maps and the Volumes of Interest (VOIs) obtained by merging together the MNI sites at which a given speech disturbance was observed, normalized on their mean the values (i.e., Z score). Both tongue- and lips-related movements fMRI maps maximally overlapped (Z = 1.05 and Z = 0.94 for lips and tongue vs. 0.16 and -1.003 for counting and naming) with the motor speech arrest seed. DES of the inferior frontal gyrus, pars opercularis and the rolandic operculum induced speech arrest proper (without apparent mentalis muscle movements). This area maximally overlapped with overt counting-related fMRI map (Z = -0.11 and Z = 0.09 for lips and tongue vs. 0.9 and 0.0006 for counting and naming). Interestingly, our fMRI maps indicated reduced Broca's area activity during silent speech compared to overt speech. Lastly, DES of the inferior frontal gyrus, pars opercularis and triangularis evoked variations of the output, i.e., dysarthria, a motor speech disorder occurring when patients cannot control the muscles used to produce articulated sounds (phonemes). Silent object naming-related fMRI map maximally overlapped (Z = -0.93 and Z = -1.04 for lips and tongue vs. -1.07 and 0.99 for counting and naming) with this seed. Speech disturbances evoked by DES may be thought of as selective interferences with specific recruitment of left inferior frontal gyrus and precentral cortex which are differentiable in terms of the specific interference induced.


Asunto(s)
Mapeo Encefálico , Neoplasias Encefálicas , Estimulación Eléctrica , Imagen por Resonancia Magnética , Habla , Humanos , Masculino , Femenino , Adulto , Habla/fisiología , Persona de Mediana Edad , Neoplasias Encefálicas/cirugía , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/fisiopatología , Estudios Retrospectivos , Glioma/cirugía , Glioma/diagnóstico por imagen , Glioma/fisiopatología , Adulto Joven , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/fisiopatología , Imagen Multimodal
6.
Sci Rep ; 13(1): 23103, 2023 12 29.
Artículo en Inglés | MEDLINE | ID: mdl-38158431

RESUMEN

Glioma is the most common primary malignant brain tumor in adults and remains an incurable disease at present. Thus, there is an urgent need for progress in finding novel molecular mechanisms that control the progression of glioma which could be used as therapeutic targets for glioma patients. The RNA binding protein cytoplasmic polyadenylate element-binding protein 2 (CPEB2) is involved in the pathogenesis of several tumors. However, the role of CPEB2 in glioma progression is unknown. In this study, the functional characterization of the role and molecular mechanism of CPEB2 in glioma were examined using a series of biological and cellular approaches in vitro and in vivo. Our work shows CPEB2 is significantly downregulated in various glioma patient cohorts. Functional characterization of CPEB2 by overexpression and knockdown revealed that it inhibits glioma cell proliferation and promotes apoptosis. CPEB2 exerts an anti-tumor effect by increasing p21 mRNA stability and inducing G1 cell cycle arrest in glioma. Overall, this work stands as the first report of CPEB2 downregulation and involvement in glioma pathogenesis, and identifies CPEB2 as an important tumor suppressor gene through targeting p21 in glioma, which revealed that CPEB2 may become a promising predictive biomarker for prognosis in glioma patients.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Glioma , Proteína Oncogénica p21(ras) , Estabilidad del ARN , Proteínas de Unión al ARN , Proteínas de Unión al ARN/sangre , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Proliferación Celular/genética , Proteína Oncogénica p21(ras)/genética , Proteína Oncogénica p21(ras)/metabolismo , Estabilidad del ARN/genética , Glioma/diagnóstico , Glioma/fisiopatología , Técnicas de Silenciamiento del Gen , Apoptosis/genética , Regulación Neoplásica de la Expresión Génica/genética , Puntos de Control del Ciclo Celular/genética , Biomarcadores de Tumor/sangre , Regulación hacia Abajo/genética , Línea Celular Tumoral , Ratones Endogámicos BALB C , Células HEK293 , Humanos , Femenino , Animales , Ratones
7.
J Biol Chem ; 299(9): 105128, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37543361

RESUMEN

Gliomas are the most prevalent primary tumor of the central nervous system. Despite advances in imaging technologies, neurosurgical techniques, and radiotherapy, a cure for high-grade glioma remains elusive. Several groups have reported that protein tyrosine phosphatase receptor type Z (PTPRZ) is highly expressed in glioblastoma, and that targeting PTPRZ attenuates tumor growth in mice. PTPRZ is modified with diverse glycan, including the PTPRZ-unique human natural killer-1 capped O-mannosyl core M2 glycans. However, the regulation and function of these unique glycans are unclear. Using CRISPR genome-editing technology, we first demonstrated that disruption of the PTPRZ gene in human glioma LN-229 cells resulted in profoundly reduced tumor growth in xenografted mice, confirming the potential of PTPRZ as a therapeutic target for glioma. Furthermore, multiple glycan analyses revealed that PTPRZ derived from glioma patients and from xenografted glioma expressed abundant levels of human natural killer-1-capped O-Man glycans via extrinsic signals. Finally, since deficiency of O-Man core M2 branching enzyme N-acetylglucosaminyltransferase IX (GnT-IX) was reported to reduce PTPRZ protein levels, we disrupted the GnT-IX gene in LN-229 cells and found a significant reduction of glioma growth both in vitro and in the xenograft model. These results suggest that the PTPR glycosylation enzyme GnT-IX may represent a promising therapeutic target for glioma.


Asunto(s)
Glioma , N-Acetilglucosaminiltransferasas , Proteínas Tirosina Fosfatasas Clase 5 Similares a Receptores , Animales , Humanos , Ratones , Encéfalo/enzimología , Encéfalo/fisiopatología , Glioma/fisiopatología , N-Acetilglucosaminiltransferasas/genética , N-Acetilglucosaminiltransferasas/metabolismo , Polisacáridos/metabolismo , Línea Celular Tumoral , Femenino , Ratones SCID , Proteínas Tirosina Fosfatasas Clase 5 Similares a Receptores/deficiencia , Proteínas Tirosina Fosfatasas Clase 5 Similares a Receptores/metabolismo , Técnicas de Silenciamiento del Gen
9.
Nature ; 619(7971): 844-850, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37380778

RESUMEN

The tumour microenvironment plays an essential role in malignancy, and neurons have emerged as a key component of the tumour microenvironment that promotes tumourigenesis across a host of cancers1,2. Recent studies on glioblastoma (GBM) highlight bidirectional signalling between tumours and neurons that propagates a vicious cycle of proliferation, synaptic integration and brain hyperactivity3-8; however, the identity of neuronal subtypes and tumour subpopulations driving this phenomenon is incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumours promote progression and widespread infiltration. Using this platform to examine GBM infiltration, we identified an activity-dependent infiltrating population present at the leading edge of mouse and human tumours that is enriched for axon guidance genes. High-throughput, in vivo screening of these genes identified SEMA4F as a key regulator of tumourigenesis and activity-dependent progression. Furthermore, SEMA4F promotes the activity-dependent infiltrating population and propagates bidirectional signalling with neurons by remodelling tumour-adjacent synapses towards brain network hyperactivity. Collectively our studies demonstrate that subsets of neurons in locations remote to primary GBM promote malignant progression, and also show new mechanisms of glioma progression that are regulated by neuronal activity.


Asunto(s)
Neoplasias Encefálicas , Carcinogénesis , Glioma , Neuronas , Microambiente Tumoral , Humanos , Encéfalo/patología , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/fisiopatología , Carcinogénesis/patología , Línea Celular Tumoral , Transformación Celular Neoplásica/patología , Glioblastoma/patología , Glioblastoma/fisiopatología , Glioma/patología , Glioma/fisiopatología , Neuronas/patología , Proliferación Celular , Sinapsis , Progresión de la Enfermedad , Animales , Ratones , Axones , Cuerpo Calloso/patología , Vías Nerviosas
10.
BMC Cancer ; 23(1): 455, 2023 May 18.
Artículo en Inglés | MEDLINE | ID: mdl-37202742

RESUMEN

BACKGROUND: PVT1, a previously uncharacterized lncRNA, was identified as a critical regulator involved in multiple functions in tumor, including cell proliferation, cell motility, angiogenesis and so on. However, the clinical significance and underlying mechanism of PVT1 was not be fully explored in glioma. METHODS: In this study, 1210 glioma samples with transcriptome data from three independent databases (CGGA RNA-seq, TCGA RNA-seq and GSE16011 cohorts) were enrolled in this study. Clinical information and genomic profiles containing somatic mutations and DNA copy numbers were collected from TCGA cohort. The R software was performed for statistical calculations and graphics. Furthermore, we validated the function of PVT1 in vitro. RESULTS: The results indicated that higher PVT1 expression was associated with aggressive progression of glioma. Cases with higher PVT1 expression always accompanied by PTEN and EGFR alteration. In addition, functional analyses and western blot results suggested that PVT1 inhibited the sensitivity of TMZ chemotherapy via JAK/STAT signaling. Meanwhile, knockdown of PVT1 increased the sensitivity of TZM chemotherapy in vitro. Finally, high PVT1 expression was associated with reduced survival time and may serve as a strong prognostic indicator for gliomas. CONCLUSIONS: This study demonstrated that PVT1 expression strongly correlated with tumor progression and chemo-resistance. PVT1 may become a potential biomarker for the diagnosis and treatment in glioma.


Asunto(s)
Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica , Glioma , ARN Largo no Codificante , Temozolomida , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Temozolomida/farmacología , Temozolomida/uso terapéutico , Resistencia a Antineoplásicos/genética , Técnicas de Silenciamiento del Gen , Carcinogénesis/genética , Regulación Neoplásica de la Expresión Génica/genética , Glioma/tratamiento farmacológico , Glioma/genética , Glioma/fisiopatología , Análisis de Supervivencia , Factores de Transcripción STAT/metabolismo , Quinasas Janus/metabolismo , Línea Celular Tumoral , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Biomarcadores de Tumor/metabolismo
11.
Neurol India ; 70(Supplement): S326-S330, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36412391

RESUMEN

Spinal dural arteriovenous fistulae (SDAVF) are most commonly idiopathic in origin but may occasionally be seen secondary to surgery, trauma, or inflammation. We report a case of 27-year-old male who came with features of a myelopathy. He was found to have an SDAVF associated with leptomeningeal spread (LMS) of a previously treated high-grade cerebral glioma. Hemorrhagic presentation of gliomas, as in this case, is due to upregulation of vascular endothelial growth factor, which has also been postulated to play a role in the development of SDAVFs. This may suggest a possible mechanism of induction of secondary SDAVFs associated with such tumors. While the coexistence of intracranial neoplasms with vascular malformations has been reported previously, this is the first case report of LMS of a high-grade glioma associated with an SDAVF.


Asunto(s)
Neoplasias Encefálicas , Malformaciones Vasculares del Sistema Nervioso Central , Glioma , Carcinomatosis Meníngea , Enfermedades de la Médula Espinal , Adulto , Humanos , Masculino , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Malformaciones Vasculares del Sistema Nervioso Central/etiología , Malformaciones Vasculares del Sistema Nervioso Central/fisiopatología , Glioma/complicaciones , Glioma/genética , Glioma/fisiopatología , Glioma/secundario , Glioma/terapia , Imagen por Resonancia Magnética , Carcinomatosis Meníngea/complicaciones , Carcinomatosis Meníngea/fisiopatología , Carcinomatosis Meníngea/secundario , Enfermedades de la Médula Espinal/etiología , Enfermedades de la Médula Espinal/genética , Enfermedades de la Médula Espinal/fisiopatología , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/fisiología , Duramadre , Invasividad Neoplásica
12.
Acta Neurochir (Wien) ; 164(8): 1995-2008, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35420374

RESUMEN

OBJECTIVE: To report our experience and investigate frequencies of adverse events and functional status from the first 5 years of performing awake surgery for gliomas in a single-center population-based setting. METHODS: We conducted a review of all patients with a glioma treated with awake surgery during the first 5 years following introduction of awake surgery at our center (February 2015 to February 2020). We assessed functional and radiological outcome, with adverse events classified according to the Landriel-Ibanez classification for neurosurgical complications, while neurological deficits were further subdivided into transient vs permanent. We sought to analyze our initial results and learning curve, as well as compare our results with literature. RESULTS: Forty-two patients were included. The median age was 38 years (range 18-66) and 13 (31%) were female. The indication for awake surgery was a presumed glioma in or near an eloquent area. The overall 30-day complication rate was 25 (59%), with 19 (45%) grade I complications, 3 (7%) grade II complications, and 3 (7%) grade III complications. Fifteen patients (36%) experienced transient neurological deficits, and 11 (26%) permanent neurological deficits. At 3-month follow-up, the Karnofsky Performance Score was 80 or higher for the entire cohort. The median extent of resection was 87%, with GTR achieved in 11 (26%). In search of potential learning curve difficulties, patients were divided into the 21 patients treated first (Early Group) versus the remaining 21 patients treated later (Late Group); no statistically significant difference in operating time, amount of tumor removed, or incidence of long-term postoperative neurological deficit was identified between groups. No awake surgery was aborted due to seizures. Comparison to the literature was limited by the diverse and unsystematic way in which previous studies have reported adverse events after awake craniotomy for gliomas. CONCLUSION: We provide a standardized report of adverse events and functional status following awake surgery for glioma during a single-center 5-year learning period, with similar rates of severe adverse events and functional outcome compared to literature without concerns of substantial learning curve difficulties. However, this comparison was flawed by non-standardized reporting of complications, highlighting a demand for more standardized reporting of adverse events after awake craniotomies.


Asunto(s)
Neoplasias Encefálicas , Craneotomía , Glioma , Adolescente , Adulto , Anciano , Neoplasias Encefálicas/fisiopatología , Neoplasias Encefálicas/cirugía , Craneotomía/efectos adversos , Craneotomía/métodos , Femenino , Estado Funcional , Glioma/fisiopatología , Glioma/cirugía , Humanos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/epidemiología , Vigilia , Adulto Joven
13.
Nat Commun ; 13(1): 328, 2022 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-35039507

RESUMEN

Historically, the study of patients with spatial neglect has provided fundamental insights into the neural basis of spatial attention. However, lesion mapping studies have been unsuccessful in establishing the potential role of associative networks spreading on the dorsal-medial axis, mainly because they are uncommonly targeted by vascular injuries. Here we combine machine learning-based lesion-symptom mapping, disconnection analyses and the longitudinal behavioral data of 128 patients with well-delineated surgical resections. The analyses show that surgical resections in a location compatible with both the supplementary and the cingulate eye fields, and disrupting the dorsal-medial fiber network, are specifically associated with severely diminished performance on a visual search task (i.e., visuo-motor exploratory neglect) with intact performance on a task probing the perceptual component of neglect. This general finding provides causal evidence for a role of the frontal-medial network in the voluntary deployment of visuo-spatial attention.


Asunto(s)
Atención/fisiología , Percepción Espacial/fisiología , Campos Visuales/fisiología , Percepción Visual/fisiología , Adulto , Conducta , Neoplasias Encefálicas/fisiopatología , Neoplasias Encefálicas/cirugía , Estudios de Casos y Controles , Femenino , Glioma/fisiopatología , Glioma/cirugía , Humanos , Masculino , Máquina de Vectores de Soporte , Sustancia Blanca/cirugía
14.
MAGMA ; 35(1): 17-27, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34910266

RESUMEN

OBJECTIVE: To evaluate the feasibility of intravoxel incoherent motion (IVIM) in assessing blood-brain barrier (BBB) integrity and microvasculature in tumoral tissue of glioma patients. METHODS: Images from 8 high-grade and 4 low-grade glioma patients were acquired on a 3 T MRI scanner. Acquisition protocol included pre- and post-contrast T1- and T2-weighted imaging, FLAIR, dynamic susceptibility contrast (DSC), and susceptibility-weighted imaging (SWI). In addition, IVIM was acquired with 15 b-values and fitted under the non-negative least square (NNLS) model to output the diffusion (D) and pseudo-diffusion (D*) coefficients, perfusion fraction (f), and f times D* (fD*) maps. RESULTS: IVIM perfusion-related maps were sensitive to (1) blood flow and perfusion alterations within the microvasculature of brain tumors, in agreement with intra-tumoral susceptibility signal (ITSS); (2) enhancing areas of BBB breakdown in agreement with DSC maps as well as areas of BBB abnormality that was not detected on DSC maps; (3) enhancing perfusion changes within edemas; (4) detecting early foci of increased perfusion within low-grade gliomas. CONCLUSION: The results suggest IVIM may be a promising approach to delineate tumor extension and progression in size, and to predict histological grade, which are clinically relevant information that characterize tumors and guide therapeutic decisions in patients with glioma.


Asunto(s)
Barrera Hematoencefálica , Glioma , Microvasos , Barrera Hematoencefálica/diagnóstico por imagen , Barrera Hematoencefálica/patología , Barrera Hematoencefálica/fisiopatología , Imagen de Difusión por Resonancia Magnética/métodos , Estudios de Factibilidad , Glioma/irrigación sanguínea , Glioma/diagnóstico por imagen , Glioma/patología , Glioma/fisiopatología , Humanos , Microcirculación , Microvasos/diagnóstico por imagen , Microvasos/patología , Movimiento (Física)
15.
J Neurooncol ; 156(1): 185-193, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34817796

RESUMEN

PURPOSE: Impaired neurocognitive function (NCF) is extremely common in patients with higher grade primary brain tumor. We previously reported evidence of genetic variants associated with NCF in glioma patients prior to treatment. However, little is known about the effect of genetic variants on NCF decline after adjuvant therapy. METHODS: Patients (N = 102) completed longitudinal NCF assessments that included measures of verbal memory, processing speed, and executive function. Testing was conducted in the postoperative period with an average follow up interval of 1.3 years. We examined polymorphisms in 580 genes related to five pathways (inflammation, DNA repair, metabolism, cognitive, and telomerase). RESULTS: Five polymorphisms were associated with longitudinal changes in processing speed and 14 polymorphisms with executive function. Change in processing speed was strongly associated with MCPH1 rs17631450 (P = 2.2 × 10-7) and CCDC26 rs7005206 (P = 9.3 × 10-7) in the telomerase pathway; while change in executive function was more strongly associated with FANCF rs1514084 (P = 2.9 × 10-6) in the DNA repair pathway and DAOA rs12428572 (P = 2.4 × 10-5) in the cognitive pathway. Joint effect analysis found significant genetic-dosage effects for longitudinal changes in processing speed (Ptrend = 1.5 × 10-10) and executive function (Ptrend = 2.1 × 10-11). In multivariable analyses, predictors of NCF decline included progressive disease, lower baseline NCF performance, and more at-risk genetic variants, after adjusting for age, sex, education, tumor location, histology, and disease progression. CONCLUSION: Our longitudinal analyses revealed that polymorphisms in telomerase, DNA repair, and cognitive pathways are independent predictors of decline in NCF in glioma patients.


Asunto(s)
Neoplasias Encefálicas , Glioma , Trastornos Neurocognitivos , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/fisiopatología , Reparación del ADN/genética , Glioma/genética , Glioma/fisiopatología , Humanos , Estudios Longitudinales , Trastornos Neurocognitivos/genética , Trastornos Neurocognitivos/fisiopatología , Pruebas Neuropsicológicas , Polimorfismo Genético , Telomerasa/genética
16.
Biomed Pharmacother ; 146: 112585, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34968923

RESUMEN

The balance between ubiquitination and deubiquitination is crucial for protein stability, function and location under physiological conditions. Dysregulation of E1/E2/E3 ligases or deubiquitinases (DUBs) results in malfunction of the ubiquitin system and is involved in many diseases. Increasing reports have indicated that ubiquitin-specific peptidases (USPs) play a part in the progression of many kinds of cancers and could be good targets for anticancer treatment. Glioma is the most common malignant tumor in the central nervous system. Clinical treatment for high-grade glioma is unsatisfactory thus far. Multiple USPs are dysregulated in glioma and have the potential to be therapeutic targets. In this review, we collected studies on the roles of USPs in glioma progression and summarized the mechanisms of USPs in glioma tumorigenesis, malignancy and chemoradiotherapy resistance.


Asunto(s)
Glioma/fisiopatología , Ubiquitina-Proteína Ligasas/fisiología , Proteasas Ubiquitina-Específicas/metabolismo , Ubiquitinación/fisiología , Animales , Autofagia/fisiología , Carcinogénesis/metabolismo , Reparación del ADN/fisiología , Resistencia a Antineoplásicos/fisiología , Humanos , Tolerancia a Radiación/fisiología , Transducción de Señal/fisiología
17.
Artículo en Inglés | MEDLINE | ID: mdl-34936295

RESUMEN

Glioma is one of the most common types of primary intracranial tumors. The relationship between triiodothyronine (T3) and glioma is not clear. This study aimed to investigate the effect of T3 on the proliferation of glioma cells and its mechanism. Cell viability was analyzed by cell counting kit 8 assay. Flow cytometry analysis was used to detect cell apoptosis and cell cycle. Thyroid hormone receptor α (THRA) and thyroid hormone receptor ß (THRB) were silenced by transfecting si-THRA and si-THRB plasmids into HS683 and A172 glioma cells. Western blot was performed to assess the protein expressions. The results indicated that triiodothyronine (T3) affected the viability, apoptosis and cell cycle of HS683 and A172 glioma cells. Cell apoptosis was significantly inhibited in si-THRA and si-THRB experimental groups. Moreover, knockdown of THRA and THRB reversed the G1 and G2 phase arrest led by T3 and induced an up-regulation of cyclin D1 expression. The phosphorylated extracellular signal-regulated kinase (p-ERK), p-AKT, and phosphorylated signal transducer and activator of transcription (p-STAT3) proteins were markedly increased by inhibiting THRA and THRB in HS683 and A172 glioma cells. T3 affected apoptosis and cell cycle of glioma cells through regulating THRA and THRB expressions. THRA and THRB may affect glioma development through regulating, at least partially, the mitogen-activated protein kinase (MAPK)/ERK and phosphoinositide 3-kinase (PI3K)/Akt signaling pathways.


Asunto(s)
Apoptosis/genética , Senescencia Celular/genética , Glioma/fisiopatología , Receptores alfa de Hormona Tiroidea/genética , Receptores beta de Hormona Tiroidea/genética , Triyodotironina/metabolismo , Línea Celular Tumoral , Silenciador del Gen , Humanos , Receptores alfa de Hormona Tiroidea/metabolismo , Receptores beta de Hormona Tiroidea/metabolismo
18.
Int J Mol Sci ; 22(23)2021 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-34884748

RESUMEN

Intramedullary spinal cord tumors are a rare and understudied cancer with poor treatment options and prognosis. Our prior study used a combination of PDGF-B, HRAS, and p53 knockdown to induce the development of high-grade glioma in the spinal cords of minipigs. In this study, we evaluate the ability of each vector alone and combinations of vectors to produce high-grade spinal cord gliomas. Eight groups of rats (n = 8/group) underwent thoracolumbar laminectomy and injection of lentiviral vector in the lateral white matter of the spinal cord. Each group received a different combination of lentiviral vectors expressing PDGF-B, a constitutively active HRAS mutant, or shRNA targeting p53, or a control vector. All animals were monitored once per week for clinical deficits for 98 days. Tissues were harvested and analyzed using hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining. Rats injected with PDGF-B+HRAS+sh-p53 (triple cocktail) exhibited statistically significant declines in all behavioral measures (Basso Beattie Bresnahan scoring, Tarlov scoring, weight, and survival rate) over time when compared to the control. Histologically, all groups except the control and those injected with sh-p53 displayed the development of tumors at the injection site, although there were differences in the rate of tumor growth and the histopathological features of the lesions between groups. Examination of immunohistochemistry revealed rats receiving triple cocktail displayed the largest and most significant increase in the Ki67 proliferation index and GFAP positivity than any other group. PDGF-B+HRAS also displayed a significant increase in the Ki67 proliferation index. Rats receiving PDGF-B alone and PDGF-B+ sh-p53 displayed more a significant increase in SOX2-positive staining than in any other group. We found that different vector combinations produced differing high-grade glioma models in rodents. The combination of all three vectors produced a model of high-grade glioma more efficiently and aggressively with respect to behavioral, physiological, and histological characteristics than the rest of the vector combinations. Thus, the present rat model of spinal cord glioma may potentially be used to evaluate therapeutic strategies in the future.


Asunto(s)
Glioma/etiología , Lentivirus/genética , Neoplasias de la Médula Espinal/etiología , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Proliferación Celular , Vectores Genéticos , Glioma/patología , Glioma/fisiopatología , Mutación , Neoplasias Experimentales/etiología , Neoplasias Experimentales/patología , Neoplasias Experimentales/fisiopatología , Proteínas Oncogénicas/genética , Proteínas Oncogénicas/metabolismo , Factor de Crecimiento Derivado de Plaquetas/genética , Factor de Crecimiento Derivado de Plaquetas/metabolismo , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/genética , Ratas , Ratas Sprague-Dawley , Neoplasias de la Médula Espinal/patología , Neoplasias de la Médula Espinal/fisiopatología , Proteína p53 Supresora de Tumor/antagonistas & inhibidores , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteínas ras/genética , Proteínas ras/metabolismo
19.
Proc Natl Acad Sci U S A ; 118(46)2021 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-34753819

RESUMEN

Recent developments in the biology of malignant gliomas have demonstrated that glioma cells interact with neurons through both paracrine signaling and electrochemical synapses. Glioma-neuron interactions consequently modulate the excitability of local neuronal circuits, and it is unclear the extent to which glioma-infiltrated cortex can meaningfully participate in neural computations. For example, gliomas may result in a local disorganization of activity that impedes the transient synchronization of neural oscillations. Alternatively, glioma-infiltrated cortex may retain the ability to engage in synchronized activity in a manner similar to normal-appearing cortex but exhibit other altered spatiotemporal patterns of activity with subsequent impact on cognitive processing. Here, we use subdural electrocorticography to sample both normal-appearing and glioma-infiltrated cortex during speech. We find that glioma-infiltrated cortex engages in synchronous activity during task performance in a manner similar to normal-appearing cortex but recruits a diffuse spatial network. On a temporal scale, we show that signals from glioma-infiltrated cortex have decreased entropy, which may affect its ability to encode information during nuanced tasks such as production of monosyllabic versus polysyllabic words. Furthermore, we show that temporal decoding strategies for distinguishing monosyllabic from polysyllabic words were feasible for signals arising from normal-appearing cortex but not from glioma-infiltrated cortex. These findings inform our understanding of cognitive processing in chronic disease states and have implications for neuromodulation and prosthetics in patients with malignant gliomas.


Asunto(s)
Neoplasias Encefálicas/fisiopatología , Glioma/fisiopatología , Habla/fisiología , Adulto , Corteza Cerebral/fisiopatología , Electrocorticografía/métodos , Humanos , Neuronas/fisiología , Lóbulo Temporal/fisiopatología
20.
Molecules ; 26(20)2021 Oct 12.
Artículo en Inglés | MEDLINE | ID: mdl-34684726

RESUMEN

Gliomas are the most common malignant brain tumors in adults, characterized by a high proliferation and invasion. The tumor microenvironment is rich in growth-promoting signals and immunomodulatory pathways, which increase the tumor's aggressiveness. In response to hypoxia and glioma therapy, the amounts of adenosine triphosphate (ATP) and adenosine diphosphate (ADP) strongly increase in the extracellular space, and the purinergic signaling is triggered by nucleotides' interaction in P2 receptors. Several cell types are present in the tumor microenvironment and can facilitate tumor growth. In fact, tumor cells can activate platelets by the ADP-P2Y12 engagement, which plays an essential role in the cancer context, protecting tumors from the immune attack and providing molecules that contribute to the growth and maintenance of a rich environment to sustain the protumor cycle. Besides platelets, the P2Y12 receptor is expressed by some tumors, such as renal carcinoma, colon carcinoma, and gliomas, being related to tumor progression. In this context, this review aims to depict the glioma microenvironment, focusing on the relationship between platelets and tumor malignancy.


Asunto(s)
Glioma/metabolismo , Receptores Purinérgicos P2Y12/metabolismo , Receptores Purinérgicos P2Y12/fisiología , Adenosina Difosfato/metabolismo , Adenosina Trifosfato/metabolismo , Plaquetas/metabolismo , Neoplasias Encefálicas/metabolismo , Glioma/fisiopatología , Humanos , Receptores Purinérgicos/metabolismo , Transducción de Señal/fisiología , Microambiente Tumoral/fisiología
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