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Communication in the form of non-verbal, social vocalization, or crying is evolutionary conserved in mammals and is impaired early in human infants that are later diagnosed with autism spectrum disorder (ASD). Defects in infant vocalization have been proposed as an early sign of ASD that may exacerbate ASD development. However, the neural mechanisms associated with early communicative deficits in ASD are not known. Here, we expressed a constitutively active mutant of Rheb (RhebS16H), which is known to upregulate two ASD core pathways, mTOR complex 1 (mTORC1) and ERK1/2, in layer (L) 2/3 pyramidal neurons of the neocortex of mice of either sex. We found that cellular mosaic expression of RhebS16H in L2/3 pyramidal neurons altered the production of isolation calls from neonatal mice. This was accompanied by an expected misplacement of neurons and dendrite overgrowth, along with an unexpected increase in spine density and length, which was associated with increased excitatory synaptic activity. This contrasted with the known decrease in spine density in RhebS16H neurons of one-month-old mice. Reducing the levels of the actin crosslinking and adaptor protein filamin A (FLNA), known to be increased downstream of ERK1/2, attenuated dendrite overgrowth and fully restored spine properties, synaptic connectivity, and the production of pup isolation calls. These findings suggest that upper-layer cortical pyramidal neurons contribute to communicative deficits in a condition known to affect two core ASD pathways and that these mechanisms are regulated by FLNA.Significance Statement An infant's cry is a form of evolutionarily conserved social communication that is altered in ASD and has been proposed as an early sign of ASD. However, the neural substrate of early communicative deficits is not known. We show that cellular mosaic expression of a constitutively active Rheb, known to upregulate two core ASD pathways, selectively in upper-layer neocortical pyramidal neurons, alters the production of pup isolation calls and synaptic connectivity. These defects were prevented by reducing the expression of the adaptor protein FLNA. This underscores the importance of a specific neuronal substrate responsible for communicative deficits and its regulation by FLNA.
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Hyperactivation of the mTOR pathway during foetal neurodevelopment alters neuron structure and function, leading to focal malformation of cortical development and intractable epilepsy. Recent evidence suggests a role for dysregulated cap-dependent translation downstream of mTOR signalling in the formation of focal malformation of cortical development and seizures. However, it is unknown whether modifying translation once the developmental pathologies are established can reverse neuronal abnormalities and seizures. Addressing these issues is crucial with regards to therapeutics because these neurodevelopmental disorders are predominantly diagnosed during childhood, when patients present with symptoms. Here, we report increased phosphorylation of the mTOR effector and translational repressor, 4E-BP1, in patient focal malformation of cortical development tissue and in a mouse model of focal malformation of cortical development. Using temporally regulated conditional gene expression systems, we found that expression of a constitutively active form of 4E-BP1 that resists phosphorylation by focal malformation of cortical development in juvenile mice reduced neuronal cytomegaly and corrected several neuronal electrophysiological alterations, including depolarized resting membrane potential, irregular firing pattern and aberrant expression of HCN4 ion channels. Further, 4E-BP1 expression in juvenile focal malformation of cortical development mice after epilepsy onset resulted in improved cortical spectral activity and decreased spontaneous seizure frequency in adults. Overall, our study uncovered a remarkable plasticity of the juvenile brain that facilitates novel therapeutic opportunities to treat focal malformation of cortical development-related epilepsy during childhood with potentially long-lasting effects in adults.
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Proteínas Adaptadoras Transductoras de Señales , Proteínas de Ciclo Celular , Epilepsia , Serina-Treonina Quinasas TOR , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Encéfalo/patología , Proteínas de Ciclo Celular/genética , Epilepsia/patología , Humanos , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/metabolismo , Ratones , Neuronas/metabolismo , Fosforilación , Convulsiones/inducido químicamente , Convulsiones/genética , Convulsiones/metabolismo , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
The release of small extracellular vesicles (sEVs) has recently been reported, but knowledge of their function in neuron development remains limited. Using LC-MS/MS, we found that sEVs released from developing cortical neurons in vitro obtained from mice of both sexes were enriched in cytoplasm, exosome, and protein-binding and DNA/RNA-binding pathways. The latter included HDAC2, which was of particular interest, because HDAC2 regulates spine development, and populations of neurons expressing different levels of HDAC2 co-exist in vivo during the period of spine growth. Here, we found that HDAC2 levels decrease in neurons as they acquire synapses and that sEVs from HDAC2-rich neurons regulate HDAC2 signaling in HDAC2-low neurons possibly through HDAC2 transfer. This regulation led to a transcriptional decrease in HDAC2 synaptic targets and the density of excitatory synapses. These data suggest that sEVs provide inductive cell-cell signaling that coordinates the development of dendritic spines via the activation of HDAC2-dependent transcriptional programs.SIGNIFICANCE STATEMENT A role of small extracellular vesicles (sEVs; also called exosomes) in neuronal development is of particular interest, because sEVs could provide a major signaling modality between developing neurons when synapses are not fully functional or immature. However, knowledge of sEVs on neuron, and more precisely spine development, is limited. We provide several lines of evidence that sEVs released from developing cortical neurons regulate the development of dendritic spines via the regulation of HDAC2 signaling. This paracrine communication is temporally restricted during development because of the age-dependent decrease in sEV release as neurons mature and acquire spines.
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Espinas Dendríticas/fisiología , Espacio Extracelular/fisiología , Histona Desacetilasa 2/genética , Histona Desacetilasa 2/fisiología , Transducción de Señal/genética , Transducción de Señal/fisiología , Animales , Citoplasma/metabolismo , Exosomas/metabolismo , Femenino , Regulación del Desarrollo de la Expresión Génica/genética , Regulación del Desarrollo de la Expresión Génica/fisiología , Masculino , Ratones , Cultivo Primario de Células , Proteómica , Sinapsis/fisiologíaRESUMEN
OBJECTIVES: This study aimed to identify the role of ferroptosis in intracranial aneurysm (IA). METHODS: GSE122897, GSE75436, GSE15629, and GSE75434 datasets were downloaded from the Gene Expression Omnibus database. The differentially expressed ferroptosis-related genes (DEFRGs) were selected to construct a diagnostic model integrating with machine learning. Then, a consensus clustering algorithm was performed to classify IA patients into distinct ferroptosis-related clusters. Functional analyses, including GO, KEGG, GSVA, and GSEA analyses, were conducted to elucidate the underlying mechanisms. ssGSEA and xCell algorithms were performed to uncover the immune characteristics. RESULTS: We identified 28 DEFRGs between IAs and controls from the GSE122897 dataset. GO and KEGG results showed that these genes were enriched in cytokine activity, ferroptosis, and the IL-17 signaling pathway. Immune analysis showed that the IAs had higher levels of immune infiltration. A four FRGs model (MT3, CDKN1A, ZEP69B, and ABCC1) was established and validated with great IA diagnostic ability. We divided the IA samples into two clusters and found that cluster 2 had a higher proportion of rupture and immune infiltration. We identified 10 ferroptosis phenotypes-related markers in IAs. CONCLUSION: Ferroptosis and the immune microenvironment are closely associated with IAs, providing a basis for understanding the IA development.
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Ferroptosis , Aneurisma Intracraneal , Humanos , Aneurisma Intracraneal/genética , Aneurisma Intracraneal/metabolismo , Ferroptosis/genética , Perfilación de la Expresión Génica , Biomarcadores/metabolismo , Transducción de SeñalRESUMEN
Nanoparticle (NP)-based cancer immunotherapy has been extensively explored. However, the efficacy of existing strategies is often limited by the lack of effective tumor-specific antigens or the inability to present costimulatory signal or both. Here, we report a novel approach to overcoming these limitations through surface coating with dendritic-tumor fusion cell membranes, which present whole repertories of tumor-associated antigens in the presence of costimulatory molecules. Because antigen-presenting and costimulatory molecules are displayed on their surface, these NPs can efficiently penetrate immune organs and activate T cells. We show that these NPs can be utilized to prevent tumor development and regress established tumors, including tumors in the brain. We demonstrate that encapsulation of immune adjuvants further improves their efficacy. Due to their significant efficacy, the whole tumor antigen-presenting costimulatory NPs have the potential to be translated into clinical applications for treatment of various cancers.
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Inmunoterapia , Nanopartículas , Neoplasias , Antígenos de Neoplasias , Biomimética , Células Dendríticas , Humanos , Neoplasias/terapiaRESUMEN
Background: The DNA damage repair (DDR) pathways play important roles for regulating cancer progression and therapeutic response. IDH mutations, well-known prognosis biomarkers for glioma, lead to hypermethylation of tumor cells and affect genes' expression. Whether IDH mutations affect glioma prognosis through influencing the expression of DDR genes remains unclear. Methods: A total of 272 DDR genes were selected for differential expression and survival analysis. The identified genes were then utilized to construct the prognosis predicting model. Results: PARPBP, PLK3, POLL and WEE1 were found differential expressed between IDH mutations carriers and wild-type carriers, and were associated with survival of low grade glioma (LGG) patients. The predicting algorithm can predicts the prognosis of LGG patients. Conclusion: IDH mutations may affect LGG prognosis through regulation of DDR pathways.
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Daño del ADN , Reparación del ADN , Perfilación de la Expresión Génica , Glioma/genética , Glioma/mortalidad , Alelos , Biomarcadores de Tumor , Metilación de ADN , Femenino , Regulación Neoplásica de la Expresión Génica , Glioma/patología , Humanos , Masculino , Mutación , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos ProporcionalesRESUMEN
OBJECTIVES: Patients with mammalian target of rapamycin (mTOR)-dependent malformations of cortical development (MCDs) associated with seizures display hyperperfusion and increased vessel density of the dysmorphic cortical tissue. Some studies have suggested that the vascular defect occurred independently of seizures. Here, we further examined whether hypervascularization occurs in animal models of global and focal MCD with and without seizures, and whether it is sensitive to the mTOR blocker, rapamycin, that is approved for epilepsy treatment in tuberous sclerosis complex. METHODS: We used two experimental models of mTOR-dependent MCD consisting of conditional transgenic mice containing Tsc1null cells in the forebrain generating a global malformation associated with seizures and of wild-type mice containing a focal malformation in the somatosensory cortex generated by in utero electroporation (IUE) that does not lead to seizures. Alterations in blood vessels and the effects of a 2-week-long rapamycin treatment on these phenotypes were assessed in juvenile mice. RESULTS: Blood vessels in both the focal and global MCDs of postnatal day 14 mice displayed significant increase in vessel density, branching index, total vessel length, and decreased tissue lacunarity. In addition, rapamycin treatment (0.5 mg/kg, every 2 days) partially rescued vessel abnormalities in the focal MCD model, but it did not ameliorate the vessel abnormalities in the global MCD model that required higher rapamycin dosage for a partial rescue. SIGNIFICANCE: Here, we identified hypervascularization in mTOR-dependent MCD in the absence of seizures in young mice, suggesting that increased angiogenesis occurs during development in parallel to alterations in corticogenesis. In addition, a predictive functional outcome is that dysplastic neurons forming MCD will have better access to oxygen and metabolic supplies via their closer proximity to blood vessels. Finally, the difference in rapamycin sensitivity between a focal and global MCD suggest that rapamycin treatment will need to be titrated to match the type of MCD.
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Malformaciones del Desarrollo Cortical/metabolismo , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Animales , Vasos Sanguíneos/patología , Tamaño de la Célula , Dendritas/patología , Electroporación , Femenino , Ratones , Ratones Transgénicos , Neovascularización Patológica/patología , Neuronas/patología , Plásmidos/genética , Embarazo , Convulsiones/tratamiento farmacológico , Convulsiones/etiología , Convulsiones/patología , Corteza Somatosensorial/patología , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Serina-Treonina Quinasas TOR/genética , Esclerosis Tuberosa/complicaciones , Esclerosis Tuberosa/tratamiento farmacológicoRESUMEN
AIM: To confirm whether the expression level of Fn14 could affect progression or prognosis of glioma patients. METHODS: Glioma cohorts in The Cancer Genome Atlas, Gene Expression Omnibus and Chinese Glioma Genome Atlas databases were comprehensively analyzed. RESULTS: Low-grade patients had lower expression level of Fn14, while patients with higher expression of Fn14 tended to harbor shorter overall survival and disease-free survival. The expression level of Fn14 was downregulated by IDH1/IDH2 mutations while its gene body methylation was upregulated. After adjusting age, the expression level of Fn14 was still significantly associated with overall survival and disease-free survival in low-grade gliomas. In a cell line data analysis, Fn14 expression was positively correlated with temozolomide dosage. CONCLUSION: Fn14 was an independent predictive biomarker for the progression and prognosis in low-grade gliomas.
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Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/patología , Glioma/patología , Receptor de TWEAK/metabolismo , Antineoplásicos Alquilantes/uso terapéutico , Biomarcadores de Tumor/genética , Encéfalo/patología , Encéfalo/cirugía , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/terapia , Línea Celular Tumoral , Quimioradioterapia Adyuvante/métodos , Metilación de ADN , Dacarbazina/análogos & derivados , Dacarbazina/uso terapéutico , Conjuntos de Datos como Asunto , Supervivencia sin Enfermedad , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica , Glioma/genética , Glioma/mortalidad , Glioma/terapia , Humanos , Isocitrato Deshidrogenasa/genética , Mutación , Clasificación del Tumor , Pronóstico , Receptor de TWEAK/genética , TemozolomidaRESUMEN
Abnormal axonal connectivity and hyperactive mTOR complex 1 (mTORC1) are shared features of several neurological disorders. Hyperactive mTORC1 alters axon length and polarity of hippocampal neurons in vitro, but the impact of hyperactive mTORC1 on axon growth in vivo and the mechanisms underlying those effects remain unclear. Using in utero electroporation during corticogenesis, we show that increasing mTORC1 activity accelerates axon growth without multiple axon formation. This was prevented by counteracting mTORC1 signaling through p70S6Ks (S6K1/2) or eukaryotic initiation factor 4E-binding protein (4E-BP1/2), which both regulate translation. In addition to regulating translational targets, S6K1 indirectly signals through GSK3ß, a regulator of axogenesis. Although blocking GSK3ß activity did not alter axon growth under physiological conditions in vivo, blocking it using a dominant-negative mutant or lithium chloride prevented mTORC1-induced accelerated axon growth. These data reveal the contribution of translational and non-translational downstream effectors such as GSK3ß to abnormal axon growth in neurodevelopmental mTORopathies and open new therapeutic options for restoring long-range connectivity.
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Axones/fisiología , Proteínas Portadoras/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Complejos Multiproteicos/metabolismo , Fosfoproteínas/metabolismo , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Animales , Axones/metabolismo , Proteínas Portadoras/genética , Proteínas de Ciclo Celular , Procesos de Crecimiento Celular , Factores Eucarióticos de Iniciación , Femenino , Regulación de la Expresión Génica , Glucógeno Sintasa Quinasa 3/genética , Glucógeno Sintasa Quinasa 3 beta , Masculino , Diana Mecanicista del Complejo 1 de la Rapamicina , Ratones , Fosfoproteínas/genética , Proteínas Quinasas S6 Ribosómicas 90-kDa/genética , Transducción de SeñalRESUMEN
Mammalian target of rapamycin (mTOR) hyperactivity in perinatal neural progenitor cells (NPCs) of tuberous sclerosis complex 1 (Tsc1) heterozygote mice leads to heterotopia and abnormal neuronal morphogenesis as seen in patients with tuberous sclerosis. Considering that pathological hyperactive mTOR also occurs in individuals carrying no genetic mutations, we examined whether increasing mTOR activity in neonatal NPCs of wild-type mice would recapitulate the above phenotypes. Electroporation of a plasmid encoding constitutively active Ras-homolog enriched in brain (Rheb(CA)) into subventricular zone NPCs increased mTOR activity in newborn cells. At 19 d post-electroporation (dpe), heterotopia and ectopic cells with a neuronal morphology were observed along the migratory path [rostral migratory stream (RMS)] and in the olfactory bulb (OB). These ectopic cells displayed action potentials and received synaptic inputs identifying them as synaptically integrated neurons. RMS heterotopias contained astrocytes, neurons, and entrapped neuroblasts. Immunostaining at 3 dpe revealed the presence of Mash1(+) Olig2(-) cells in the migratory route accompanied by ectopic neuronal differentiation and altered direction and speed of neuroblast migration at 7 dpe, suggesting a non-cell-autonomous disruption of migration. At >19 dpe, newborn Rheb(CA)-expressing neurons displayed altered distribution and formed micronodules in the OB. In addition, they displayed increased dendritic complexity along with altered membrane biophysics and increased frequency of GABAergic synaptic inputs. OB heterotopia, micronodules, and dendrite hypertrophy were notably prevented by rapamycin treatment, suggesting their mTOR dependence. Collectively, these data show that increasing mTOR activity in neonatal NPCs of wild-type mice recapitulate the pathologies observed in Tsc1 mutant mice. In addition, increased mTOR activity in individuals without known mutations could significantly impact neurogenesis and circuit formation.
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Dendritas/metabolismo , Proteínas de Unión al GTP Monoméricas/metabolismo , Células-Madre Neurales/metabolismo , Neuronas/metabolismo , Neuropéptidos/metabolismo , Bulbo Olfatorio/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Animales , Animales Recién Nacidos , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/fisiología , Aumento de la Célula/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Movimiento Celular/fisiología , Ventrículos Cerebrales/metabolismo , Ventrículos Cerebrales/patología , Dendritas/efectos de los fármacos , Dendritas/patología , Electroporación/métodos , Femenino , Hipertrofia/patología , Masculino , Ratones , Proteínas de Unión al GTP Monoméricas/fisiología , Células-Madre Neurales/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Neurogénesis/fisiología , Neuronas/efectos de los fármacos , Neuronas/patología , Neuropéptidos/fisiología , Bulbo Olfatorio/efectos de los fármacos , Bulbo Olfatorio/patología , Proteína Homóloga de Ras Enriquecida en el Cerebro , Sirolimus/farmacología , Células Madre/efectos de los fármacos , Células Madre/metabolismoRESUMEN
Intracranial aneurysm (IA) is the most prevalent type of cerebral vascular disease causing life-threatening subarachnoid hemorrhages (SAH). A long-term vascular structure remodeling is considered as the main pathophysiological feature of IAs. However, the causal factors triggering the pathophysiological process are not clear. Recently, the abnormalities of peripheral circulating proteins and metabolites have been found in IAs patients and associated with the ruptures. We comprehensively investigated the potential causal relationship between blood metabolites and proteins and IAs using the mendelian randomization (MR) analysis. We applied two-sample MR to explore the potential causal association between peripheral circulating metabolites (191 blood metabolites) and proteins (1398 proteins) and IAs using data from the FinnGen study and the GWAS datasets published by Bakker et al. We identified palmitoylcarnitine, stearoylcarnitine and 2-tetradecenoylcarnitine as causal contributors of IAs and ruptures. Further two-step mediation MR analysis suggested that hypertension as one of the contributors of IAs and ruptures mediated the causal relationship between palmitoylcarnitine, stearoylcarnitine and 2-tetradecenoylcarnitine and IAs. Together, our study demonstrates that blood metabolic palmitoylcarnitine, stearoylcarnitine and 2-tetradecenoylcarnitine are causally linked to the formation and rupture of IAs. Hypertension partially mediates the causal effects.
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BACKGROUND: Besides the hallmark of H3K27M mutation, aberrant amplifications of receptor tyrosine kinases (RTKs) are commonly observed in diffuse midline glioma (DMG), a highly malignant brain tumor with dismal prognosis. Here, we intended to evaluate the efficacy and safety of a multitarget RTK inhibitor anlotinib in patients with H3K27M-DMG. METHODS: A total of 40 newly diagnosed H3K27M-DMG patients including 15 with anlotinib and 25 without anlotinib treatment were retrospectively enrolled in this cohort. Progression-free survival (PFS), overall survival (OS), and toxicities were assessed and compared. RESULTS: The median PFS and OS of all patients in this cohort were 8.5 months (95% CI, 6.5-11.3) and 15.5 months (95% CI, 12.6-17.1), respectively. According to the Response Assessment in Neuro-Oncology (RANO) criteria, the disease control rate in the anlotinib group [93.3%, 95% confidence interval (CI), 70.2-98.8] was significantly higher than those without anlotinib (64%, 95% CI: 40.5-79.8, p = 0.039). The median PFS of patients with and without anlotinib was 11.6 months (95% CI, 7.8-14.3) and 6.4 months (95% CI, 4.3-10.3), respectively. Both the median PFS and OS of DMG patients treated with anlotinib were longer than those without anlotinib in the infratentorial patients (PFS: 10.3 vs. 5.4 months, p = 0.006; OS: 16.6 vs. 8.7 months, p = 0.016). Multivariate analysis also indicated anlotinib (HR: 0.243, 95% CI: 0.066-0.896, p = 0.034) was an independent prognosticator for longer OS in the infratentorial subgroup. In addition, the adverse events of anlotinib administration were tolerable in the whole cohort. CONCLUSIONS: This study first reported that anlotinib combined with Stupp regimen is a safe and feasible regimen for newly diagnosed patients with H3K27M-DMG. Further, anlotinib showed significant efficacy for H3K27M-DMG located in the infratentorial region.
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Neoplasias Encefálicas , Glioma , Indoles , Mutación , Quinolinas , Temozolomida , Humanos , Masculino , Indoles/uso terapéutico , Indoles/administración & dosificación , Quinolinas/uso terapéutico , Quinolinas/administración & dosificación , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Adulto , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/tratamiento farmacológico , Glioma/tratamiento farmacológico , Glioma/genética , Temozolomida/uso terapéutico , Temozolomida/administración & dosificación , Adulto Joven , Estudios de Cohortes , Adolescente , Quimioradioterapia/métodos , AncianoRESUMEN
Predicting the interaction affinity between drugs and target proteins is crucial for rapid and accurate drug discovery and repositioning. Therefore, more accurate prediction of DTA has become a key area of research in the field of drug discovery and drug repositioning. However, traditional experimental methods have disadvantages such as long operation cycles, high manpower requirements, and high economic costs, making it difficult to predict specific interactions between drugs and target proteins quickly and accurately. Some methods mainly use the SMILES sequence of drugs and the primary structure of proteins as inputs, ignoring the graph information such as bond encoding, degree centrality encoding, spatial encoding of drug molecule graphs, and the structural information of proteins such as secondary structure and accessible surface area. Moreover, previous methods were based on protein sequences to learn feature representations, neglecting the completeness of information. To address the completeness of drug and protein structure information, we propose a Transformer graph-based early fusion research approach for drug-target affinity prediction (GEFormerDTA). Our method reduces prediction errors caused by insufficient feature learning. Experimental results on Davis and KIBA datasets showed a better prediction of drugtarget affinity than existing affinity prediction methods.
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Descubrimiento de Drogas , Reposicionamiento de Medicamentos , Secuencia de Aminoácidos , Suministros de Energía Eléctrica , AprendizajeRESUMEN
Glioma is the most prevalent type of neurological malignancies. Despite decades of efforts in neurosurgery, chemotherapy and radiation therapy, glioma remains one of the most treatment-resistant brain tumors with unfavorable outcomes. Recent progresses in genomic and epigenetic profiling have revealed new concepts of genetic events involved in the etiology of gliomas in humans, meanwhile, revolutionary technologies in gene editing and delivery allows to code these genetic "events" in animals to genetically engineer glioma models. This approach models the initiation and progression of gliomas in a natural microenvironment with an intact immune system and facilitates probing therapeutic strategies. In this review, we focus on recent advances in in vivo electroporation-based glioma modeling and outline the established genetically engineered glioma models (GEGMs).
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Neoplasias Encefálicas , Glioma , Animales , Humanos , Glioma/tratamiento farmacológico , Neoplasias Encefálicas/patología , Ingeniería Genética , Electroporación , Sistema Inmunológico , Microambiente TumoralRESUMEN
AIMS: H3K27M-mutant diffuse midline glioma (DMG) is a rare and aggressive central nervous system tumor. The biological behavior, clinicopathological characteristics, and prognostic factors of DMG have not yet been completely uncovered, especially in adult patients. This study aims to investigate the clinicopathological characteristics and identify prognostic factors of H3K27M-mutant DMG in pediatric and adult patients, respectively. METHODS: A total of 171 patients with H3K27M-mutant DMG were included in the study. The clinicopathological characteristics of the patients were analyzed and stratified based on age. The Cox proportional hazard model was used to determine the independent prognostic factors in pediatric and adult subgroups. RESULTS: The median overall survival (OS) for the entire cohort was 9.0 months. Significant differences were found in some clinicopathological characteristics between children and adults. The median OS was also significantly different between the pediatric and adult subgroups, with 7.1 months for children and 12.3 months for adults (p < 0.001). In the overall population, the multivariate analysis identified adult patients, single lesion, concurrent chemoradiotherapy/radiotherapy, and intact ATRX expression as independent favorable prognostic factors. In the age-stratified subgroups, the prognostic factors varied between children and adults, with intact ATRX expression and single lesion being independent favorable prognostic factors in adults, while infratentorial localization was significantly associated with worse prognosis in children. CONCLUSIONS: The differences in clinicopathological features and prognostic factors between pediatric and adult patients with H3K27M-mutant DMG suggest the need for further clinical and molecular stratification based on age.
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Neoplasias Encefálicas , Glioma , Humanos , Niño , Adulto , Glioma/genética , Glioma/terapia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/metabolismo , Histonas/genética , Mutación/genética , PronósticoRESUMEN
BACKGROUND: H3K27M mutated diffuse midline gliomas (DMGs) are extremely aggressive and the leading cause of cancer-related deaths in pediatric brain tumors with 5-year survival <1%. Radiotherapy is the only established adjuvant treatment of H3K27M DMGs; however, the radio-resistance is commonly observed. METHODS: We summarized current understandings of the molecular responses of H3K27M DMGs to radiotherapy and provide crucial insights into current advances in radiosensitivity enhancement. RESULTS: Ionizing radiation (IR) can mainly inhibit tumor cell growth by inducing DNA damage regulated by the cell cycle checkpoints and DNA damage repair (DDR) system. In H3K27M DMGs, the aberrant genetic and epigenetic changes, stemness genotype, and epithelial-mesenchymal transition (EMT) disrupt the cell cycle checkpoints and DDR system by altering the associated regulatory signaling pathways, which leads to the development of radio-resistance. CONCLUSIONS: The advances in mechanisms of radio-resistance in H3K27M DMGs promote the potential targets to enhance the sensitivity to radiotherapy.
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Neoplasias Encefálicas , Glioma , Niño , Humanos , Glioma/genética , Glioma/radioterapia , Glioma/patología , Histonas/genética , Mutación/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/patologíaRESUMEN
Background: COVID-19 could develop severe respiratory symptoms in certain infected patients, especially in the patients with immune disorders. Gut microbiome and plasma metabolome act important immunological modulators in the human body and could contribute to the immune responses impacting the progression of COVID-19. However, the causal relationship between specific intestinal bacteria, metabolites and severe COVID-19 remains not clear. Methods: Based on two-sample Mendelian randomization (MR) framework, the causal effects of 131 intestinal taxa and 452 plasma metabolites on severe COVID-19 were evaluated. Single nucleotide polymorphisms (SNPs) strongly associated with the abundance of intestinal taxa and the concentration of plasma metabolites had been utilized as the instrument variables to infer whether they were causal factors of severe COVID-19. In addition, mediation analysis was conducted to find the potential association between the taxon and metabolite, and further colocalization analysis had been performed to validate the causal relationships. Results: MR analysis identified 13 taxa and 53 metabolites, which were significantly associated with severe COVID-19 as causal factors. Mediation analysis revealed 11 mediated relationships. Myo-inositol, 2-stearoylglycerophosphocholine, and alpha-glutamyltyrosine, potentially contributed to the association of Howardella and Ruminiclostridium 6 with severe COVID-19, respectively. Butyrivibrio and Ruminococcus gnavus could mediate the association of myo-inositol and N-acetylalanine, respectively. In addition, Ruminococcus torques abundance was colocalized with severe COVID-19 (PP.H4 = 0.77) and the colon expression of permeability related protein RASIP1 (PP.H4 = 0.95). Conclusions: Our study highlights the potential causal relationships between gut microbiome, plasma metabolome and severe COVID-19, which potentially serve as clinical biomarkers for risk stratification and prognostication and benefit the mechanism mechanistic investigation of severe COVID-19.
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COVID-19 , Microbioma Gastrointestinal , Humanos , Análisis de la Aleatorización Mendeliana , Análisis de Mediación , MetabolomaRESUMEN
Brain metastasis (BM) genetically diverges from the primary tumor in non-small-cell lung cancer (NSCLC). Hence, accurately capturing clinically relevant alterations is pivotal for the delivery of targeted therapies. Circulating tumor DNA (ctDNA) sequencing has emerged as a promising liquid biopsy in the biomarker-based clinical management of recurrent and extracranial metastatic NSCLC. However, the absence of simultaneous sequencing data from brain metastatic sites prevents the definitive evaluation of the efficacy of ctDNA in representing genetic profiles in BM. Here, we performed parallel genomic comparisons between matched BM and primary tumor DNA, plasma ctDNA, and cerebrospinal fluid (CSF) ctDNA. The results indicated that CSF ctDNA had a greater ability than plasma ctDNA to comprehensively represent the mutational landscape of BM, with CSF ctDNA detecting all BM mutations in 83.33% of patients, while plasma ctDNA was only 27.78%. Mutant allele frequency (MAF) in CSF ctDNA was highly correlated with the tumor size of BM (r = 0.95), and the mean MAF in CSF ctDNA was higher than that in plasma ctDNA (38.05% vs. 4.57%, respectively). MAF and tumor mutational burden in CSF ctDNA were strongly associated with those in BM (r = 0.96 and 0.97, respectively). Of note, CSF ctDNA had significantly higher concordance with BM than plasma ctDNA (99.33% vs. 67.44%), facilitating the identification of clinically relevant mutations. Moreover, we found that plasma ctDNA has stronger profiling performance, with a concordance of 93.01% in multiple brain metastases, equivalent to CSF ctDNA. Collectively, our study indicates that CSF ctDNA is superior to plasma ctDNA in accurately representing the profiling of single BM. Plasma ctDNA could be an alternative liquid biopsy material to be applied in multiple brain metastatic NSCLC.
Asunto(s)
Neoplasias Encefálicas , Carcinoma de Pulmón de Células no Pequeñas , ADN Tumoral Circulante , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , ADN Tumoral Circulante/genética , Neoplasias Pulmonares/patología , ADN de Neoplasias , Mutación/genética , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/genéticaRESUMEN
Tobacco smoking is associated with increased risks of nearly 20 types of cancer. Although the association between smoking and gliomas, the most prevalent type of adult brain tumor, is still unconclusive, here, we found that the frequency of NF1 mutations was significantly increased in the glioma patients with smoking history compared to non-smoking patients (24% vs. 10%, P = 0.021). NF1 acts as a tumor suppressor gene is highly mutated in gliomas. The TCGA data analysis indicated that glioma patients carrying NF1 somatic mutations have worse overall survival (median survival time: smoking 19.9 months vs. non-smoking 36.8 month; P = 0.0018). In addition, we revealed that the NF1 and IDH1 mutations were mutually exclusive suggesting NF1 mutation has independent molecular mechanism involved in glioma biology.
RESUMEN
A set of semantic similarity calculation methods combining full-text text and domain knowledge topics is proposed for the current study of entity association relations such as disease-gene in medical texts combined with topics in knowledge discovery, which is insufficient to reveal the deep semantic association relations of medical domain knowledge at topic level. Taking urinary infections in elderly inpatients as the research subject, word embedding representation of word vectors and topic vectors is performed by the TWE model, and similarity calculation is performed by combining text and domain knowledge topics based on Siamese Network framework. The urinary microbiological culture results of both groups were dominated by Escherichia coli, accounting for 34.65% and 47.92%, respectively; the use of antimicrobial drugs in the symptomatic urinary infection group was 94.19% higher than that in the asymptomatic bacteriuria group, 77.27% (x 2 = 8.158, P=0.004).