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Strand selection is a critical step in microRNA (miRNA) biogenesis. Although the dominant strand may change depending on cellular contexts, the molecular mechanism and physiological significance of such alternative strand selection (or "arm switching") remain elusive. Here we find miR-324 to be one of the strongly regulated miRNAs by arm switching and identify the terminal uridylyl transferases TUT4 and TUT7 to be the key regulators. Uridylation of pre-miR-324 by TUT4/7 re-positions DICER on the pre-miRNA and shifts the cleavage site. This alternative processing produces a duplex with a different terminus from which the 3' strand (3p) is selected instead of the 5' strand (5p). In glioblastoma, the TUT4/7 and 3p levels are upregulated, whereas the 5p level is reduced. Manipulation of the strand ratio is sufficient to impair glioblastoma cell proliferation. This study uncovers a role of uridylation as a molecular switch in alternative strand selection and implicates its therapeutic potential.
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MicroARNs/metabolismo , UDP-Glucosa-Hexosa-1-Fosfato Uridiltransferasa/metabolismo , Animales , Línea Celular Tumoral , Proliferación Celular , ARN Helicasas DEAD-box/metabolismo , Proteínas de Unión al ADN/metabolismo , Femenino , Humanos , Ratones , MicroARNs/genética , Cultivo Primario de Células , ARN Nucleotidiltransferasas/metabolismo , Ribonucleasa III/metabolismoRESUMEN
Glioblastoma (GBM) is a devastating and incurable brain tumour, with a median overall survival of fifteen months1,2. Identifying the cell of origin that harbours mutations that drive GBM could provide a fundamental basis for understanding disease progression and developing new treatments. Given that the accumulation of somatic mutations has been implicated in gliomagenesis, studies have suggested that neural stem cells (NSCs), with their self-renewal and proliferative capacities, in the subventricular zone (SVZ) of the adult human brain may be the cells from which GBM originates3-5. However, there is a lack of direct genetic evidence from human patients with GBM4,6-10. Here we describe direct molecular genetic evidence from patient brain tissue and genome-edited mouse models that show astrocyte-like NSCs in the SVZ to be the cell of origin that contains the driver mutations of human GBM. First, we performed deep sequencing of triple-matched tissues, consisting of (i) normal SVZ tissue away from the tumour mass, (ii) tumour tissue, and (iii) normal cortical tissue (or blood), from 28 patients with isocitrate dehydrogenase (IDH) wild-type GBM or other types of brain tumour. We found that normal SVZ tissue away from the tumour in 56.3% of patients with wild-type IDH GBM contained low-level GBM driver mutations (down to approximately 1% of the mutational burden) that were observed at high levels in their matching tumours. Moreover, by single-cell sequencing and laser microdissection analysis of patient brain tissue and genome editing of a mouse model, we found that astrocyte-like NSCs that carry driver mutations migrate from the SVZ and lead to the development of high-grade malignant gliomas in distant brain regions. Together, our results show that NSCs in human SVZ tissue are the cells of origin that contain the driver mutations of GBM.
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Glioblastoma/genética , Glioblastoma/patología , Ventrículos Laterales/patología , Mutación , Animales , Astrocitos/metabolismo , Astrocitos/patología , Progresión de la Enfermedad , Edición Génica , Genoma/genética , Glioblastoma/enzimología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Isocitrato Deshidrogenasa/genética , Ventrículos Laterales/metabolismo , Ratones , Reproducibilidad de los Resultados , Análisis de la Célula IndividualRESUMEN
BACKGROUND: Glioblastoma (GBM), one of the most lethal tumors, exhibits a highly infiltrative phenotype. Here, we identified transcription factors (TFs) that collectively modulate invasion-related genes in GBM. METHODS: The invasiveness of tumorspheres (TSs) were quantified using collagen-based 3D invasion assays. TF activities were quantified by enrichment analysis using GBM transcriptome, and confirmed by cell-magnified analysis of proteome imaging. Invasion-associated TFs were knocked down using siRNA or shRNA, and TSs were orthotopically implanted into mice. RESULTS: After classifying 23 patient-derived GBM TSs into low- and high-invasion groups, we identified active TFs in each group-PCBP1 for low invasion, and STAT3 and SRF for high invasion. Knockdown of these TFs reversed the phenotype and invasion-associated-marker expression of GBM TSs. Notably, MRI revealed consistent patterns of invasiveness between TSs and the originating tumors, with an association between high invasiveness and poor prognosis. Compared to controls, mice implanted with STAT3- or SRF-downregulated GBM TSs showed reduced normal tissue infiltration and tumor growth, and prolonged survival, indicating a therapeutic response. CONCLUSIONS: Our integrative transcriptome analysis revealed three invasion-associated TFs in GBM. Based on the relationship among the transcriptional program, invasive phenotype, and prognosis, we suggest these TFs as potential targets for GBM therapy.
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Neoplasias Encefálicas , Glioblastoma , Animales , Humanos , Ratones , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular , Perfilación de la Expresión Génica , Glioblastoma/diagnóstico por imagen , Glioblastoma/genética , Glioblastoma/tratamiento farmacológico , Invasividad Neoplásica/patología , Pronóstico , ARN Interferente Pequeño , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismoRESUMEN
Ferroptosis is an iron-dependent regulated necrosis mediated by lipid peroxidation. Cancer cells survive under metabolic stress conditions by altering lipid metabolism, which may alter their sensitivity to ferroptosis. However, the association between lipid metabolism and ferroptosis is not completely understood. In this study, we found that the expression of elongation of very long-chain fatty acid protein 5 (ELOVL5) and fatty acid desaturase 1 (FADS1) is up-regulated in mesenchymal-type gastric cancer cells (GCs), leading to ferroptosis sensitization. In contrast, these enzymes are silenced by DNA methylation in intestinal-type GCs, rendering cells resistant to ferroptosis. Lipid profiling and isotope tracing analyses revealed that intestinal-type GCs are unable to generate arachidonic acid (AA) and adrenic acid (AdA) from linoleic acid. AA supplementation of intestinal-type GCs restores their sensitivity to ferroptosis. Based on these data, the polyunsaturated fatty acid (PUFA) biosynthesis pathway plays an essential role in ferroptosis; thus, this pathway potentially represents a marker for predicting the efficacy of ferroptosis-mediated cancer therapy.
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Ácidos Grasos Insaturados/biosíntesis , Ferroptosis/fisiología , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Ácido Araquidónico/genética , Ácido Araquidónico/metabolismo , Ácido Araquidónico/farmacología , Carbolinas/farmacología , Línea Celular Tumoral , Metilación de ADN , delta-5 Desaturasa de Ácido Graso , Elementos de Facilitación Genéticos , Ácido Graso Desaturasas/genética , Ácido Graso Desaturasas/metabolismo , Elongasas de Ácidos Grasos/genética , Elongasas de Ácidos Grasos/metabolismo , Ácidos Grasos Insaturados/genética , Ácidos Grasos Insaturados/metabolismo , Ferroptosis/efectos de los fármacos , Ferroptosis/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Metabolismo de los Lípidos/genética , Regiones Promotoras Genéticas , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/patologíaRESUMEN
INTRODUCTION: The importance of fatty acid oxidation (FAO) in the bioenergetics of glioblastoma (GBM) is being realized. Etomoxir (ETO), a carnitine palmitoyltransferase 1 (CPT1) inhibitor exerts cytotoxic effects in GBM, which involve interrupting the FAO pathway. We hypothesized that FAO inhibition could affect the outcomes of current standard temozolomide (TMZ) chemotherapy against GBM. METHODS: The FAO-related gene expression was compared between GBM and the tumor-free cortex. Using four different GBM tumorspheres (TSs), the effects of ETO and/or TMZ was analyzed on cell viability, tricarboxylate (TCA) cycle intermediates and adenosine triphosphate (ATP) production to assess metabolic changes. Alterations in tumor stemness, invasiveness, and associated transcriptional changes were also measured. Mouse orthotopic xenograft model was used to elucidate the combinatory effect of TMZ and ETO. RESULTS: GBM tissues exhibited overexpression of FAO-related genes, especially CPT1A, compared to the tumor-free cortex. The combined use of ETO and TMZ further inhibited TCA cycle and ATP production than single uses. This combination treatment showed superior suppression effects compared to treatment with individual agents on the viability, stemness, and invasiveness of GBM TSs, as well as better downregulation of FAO-related gene expression. The results of in vivo study showed prolonged survival outcomes in the combination treatment group. CONCLUSION: ETO, an FAO inhibitor, causes a lethal energy reduction in the GBM TSs. When used in combination with TMZ, ETO effectively reduces GBM cell stemness and invasiveness and further improves survival. These results suggest a potential novel treatment option for GBM.
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PURPOSE: Glioblastoma (GBM) is a rapidly growing tumor in the central nervous system with altered metabolism. Depleting the bioenergetics of tumors with biguanides have been suggested as an effective therapeutic approach for treating GBMs. The purpose of this study was to determine the effects of IM1761065, a novel biguanide with improved pharmacokinetics, on GBM-tumorspheres (TSs). METHODS: The biological activities of IM1761065 on GBM-TSs, including their effects on viability, ATP levels, cell cycle, stemness, invasive properties, and transcriptomes were examined. The in vivo efficacy of IM1761065 was tested in a mouse orthotopic xenograft model. RESULTS: IM1761065 decreased the viability and ATP levels of GBM-TSs in a dose-dependent manner, and reduced basal and spare respiratory capacity in patient-derived GBM-TS, as measured by the oxygen consumption rate. Sphere formation, expression of stemness-related proteins, and invasive capacity of GBM-TSs were also significantly suppressed by IM1761065. A gene-ontology comparison of IM1761065-treated groups showed that the expression levels of stemness-related, epithelial mesenchymal transition-related, and mitochondrial complex I genes were also significantly downregulated by IM1761065. An orthotopic xenograft mouse model showed decreased bioluminescence in IM1761065-treated cell-injected mice at 5 weeks. IM1761065-treated group showed longer survival than the control group (P = 0.0289, log-rank test). CONCLUSION: IM1761065 is a potent inhibitor of oxidative phosphorylation. The inhibitory effect of IM1761065 on the bioenergetics of GBM-TS suggests that this novel compound could be used as a new drug for the treatment of GBM.
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Biguanidas , Neoplasias Encefálicas , Metabolismo Energético , Glioblastoma , Adenosina Trifosfato/metabolismo , Animales , Biguanidas/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Línea Celular Tumoral , Metabolismo Energético/efectos de los fármacos , Glioblastoma/tratamiento farmacológico , Glioblastoma/metabolismo , Glioblastoma/patología , Humanos , Ratones , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: Limited treatment options are currently available for glioblastoma (GBM), an extremely lethal type of brain cancer. For a variety of tumor types, bioenergetic deprivation through inhibition of cancer-specific metabolic pathways has proven to be an effective therapeutic strategy. Here, we evaluated the therapeutic effects and underlying mechanisms of dual inhibition of carnitine palmitoyltransferase 1A (CPT1A) and glucose-6-phosphate dehydrogenase (G6PD) critical for fatty acid oxidation (FAO) and the pentose phosphate pathway (PPP), respectively, against GBM tumorspheres (TSs). METHODS: Therapeutic efficacy against GBM TSs was determined by assessing cell viability, neurosphere formation, and 3D invasion. Liquid chromatography-mass spectrometry (LC-MS) and RNA sequencing were employed for metabolite and gene expression profiling, respectively. Anticancer efficacy in vivo was examined using an orthotopic xenograft model. RESULTS: CPT1A and G6PD were highly expressed in GBM tumor tissues. Notably, siRNA-mediated knockdown of both genes led to reduced viability, ATP levels, and expression of genes associated with stemness and invasiveness. Similar results were obtained upon combined treatment with etomoxir and dehydroepiandrosterone (DHEA). Transcriptome analyses further confirmed these results. Data from LC-MS analysis showed that this treatment regimen induced a considerable reduction in the levels of metabolites associated with the TCA cycle and PPP. Additionally, the combination of etomoxir and DHEA inhibited tumor growth and extended survival in orthotopic xenograft model mice. CONCLUSION: Our collective findings support the utility of dual suppression of CPT1A and G6PD with selective inhibitors, etomoxir and DHEA, as an efficacious therapeutic approach for GBM.
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Glioblastoma , Animales , Humanos , Ratones , Carnitina O-Palmitoiltransferasa/antagonistas & inhibidores , Carnitina O-Palmitoiltransferasa/genética , Carnitina O-Palmitoiltransferasa/metabolismo , Línea Celular Tumoral , Deshidroepiandrosterona/uso terapéutico , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Glucosafosfato Deshidrogenasa/antagonistas & inhibidores , Glucosafosfato Deshidrogenasa/genética , Glucosafosfato Deshidrogenasa/metabolismo , Células Madre Neoplásicas/efectos de los fármacos , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patologíaRESUMEN
BACKGROUND: Previous genomewide association studies (GWASs), single nucleotide polymorphisms (SNPs) on cyclin-dependent kinase inhibitor 2 A (CDKN2A), cyclin-dependent kinase inhibitor 2B (CDKN2B), and cyclin-dependent kinase inhibitor 2B antisense RNA1 (CDKN2B-AS1) were reported as risk loci for glioma, a subgroup of the brain tumor. To further characterize this association with the risk of brain tumors in a Korean population, we performed a fine-mapping association study of CDKN2A, CDKN2B, and CDKN2B-AS1. METHODS AND RESULTS: A total of 17 SNPs were selected and genotyped in 1,439 subjects which were comprised of 959 patients (pituitary adenoma 335; glioma 324; meningioma 300) and 480 population controls (PCs). We discovered that a 3'untranslated region (3'UTR) variant, rs181031884 of CDKN2B (Asian-specific variant), had significant association with the risk of pituitary adenoma (PA) (Odds ratio = 0.58, P = 0.00003). Also, rs181031884 appeared as an independent causal variant among the significant variants in CDKN2A and CDKN2B, and showed dose-dependent effects on PA. CONCLUSIONS: Although further studies are needed to verify the impact of this variant on PA susceptibility, our results may help to understand CDKN2B polymorphism and the risk of PA.
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Glioma , Neoplasias Hipofisarias , ARN Largo no Codificante , Humanos , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Regiones no Traducidas 3'/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Neoplasias Hipofisarias/genética , Polimorfismo de Nucleótido Simple/genética , ARN Largo no Codificante/genética , Predisposición Genética a la EnfermedadRESUMEN
BACKGROUND: Driver genes of GBM may be crucial for the onset of isocitrate dehydrogenase (IDH)-wildtype (WT) glioblastoma (GBM). However, it is still unknown whether the genes are expressed in the identical cluster of cells. Here, we have examined the gene expression patterns of GBM tissues and patient-derived tumorspheres (TSs) and aimed to find a progression-related gene. METHODS: We retrospectively collected primary IDH-WT GBM tissue samples (n = 58) and tumor-free cortical tissue samples (control, n = 20). TSs are isolated from the IDH-WT GBM tissue with B27 neurobasal medium. Associations among the driver genes were explored in the bulk tissue, bulk cell, and a single cell RNAsequencing techniques (scRNAseq) considering the alteration status of TP53, PTEN, EGFR, and TERT promoter as well as MGMT promoter methylation. Transcriptomic perturbation by temozolomide (TMZ) was examined in the two TSs. RESULTS: We comprehensively compared the gene expression of the known driver genes as well as MGMT, PTPRZ1, or IDH1. Bulk RNAseq databases of the primary GBM tissue revealed a significant association between TERT and TP53 (p < 0.001, R = 0.28) and its association increased in the recurrent tumor (p < 0.001, R = 0.86). TSs reflected the tissue-level patterns of association between the two genes (p < 0.01, R = 0.59, n = 20). A scRNAseq data of a TS revealed the TERT and TP53 expressing cells are in a same single cell cluster. The driver-enriched cluster dominantly expressed the glioma-associated long noncoding RNAs. Most of the driver-associated genes were downregulated after TMZ except IGFBP5. CONCLUSIONS: GBM tissue level expression patterns of EGFR, TERT, PTEN, IDH1, PTPRZ1, and MGMT are observed in the GBM TSs. The driver gene-associated cluster of the GBM single cells were enriched with the glioma-associated long noncoding RNAs.
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Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/genética , Glioblastoma/genética , Humanos , Isocitrato Deshidrogenasa/genética , Mutación/genética , Recurrencia Local de Neoplasia , Pronóstico , Proteínas Tirosina Fosfatasas Clase 5 Similares a Receptores , Estudios RetrospectivosRESUMEN
BACKGROUND: Gastric cancer is a considerable burden for worldwide patients. And diffuse gastric cancer is the most insidious subgroup with poor survival. The phenotypic characterization of the diffuse gastric cancer cell line can be useful for gastric cancer researchers. In this article, we aimed to characterize the diffuse gastric cancer cells with MRI and transcriptomic data. We hypothesized that gene expression pattern is associated with the phenotype of the cells and that the heterogeneous enhancement pattern and the high tumorigenicity of SNU484 can be modulated by the perturbation of the highly expressed gene. METHODS: We evaluated the 9.4 T magnetic resonance imaging and transcriptomic data of the orthotopic mice models from diffuse gastric cancer cells such as SNU484, Hs746T, SNU668, and KATO III. We included MKN74 as an intestinal cancer control cell. After comprehensive analysis integrating MRI and transcriptomic data, we selected CD34 and validated the effect by shRNA in the BALB/c nude mice models. RESULTS: SNU484, SNU668, Hs746T, and MKN74 formed orthotopic tumors by the 5 weeks after cell injection. The diffuse phenotype was found in the SNU484 and Hs746T. SNU484 was the only tumor showing the heterogeneous enhancement pattern on T2 images with a high level of CD34 expression. Knockdown of CD34 decreased the round-void shape in the H&E staining (P = 0.028), the heterogeneous T2 enhancement, and orthotopic tumorigenicity (100% vs 66.7%). The RNAseq showed that the suppressed CD34 is associated with the downregulated gene-sets of the extracellular matrix remodeling. CONCLUSION: Suppression of CD34 in the human-originated gastric cancer cell suggests that it is important for the round-void histologic shape, heterogeneous enhancement pattern on MRI, and the growth of gastric cancer cell line.
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Antígenos CD34/genética , Perfilación de la Expresión Génica/métodos , Neoplasias Gástricas/diagnóstico por imagen , Adulto , Anciano , Anciano de 80 o más Años , Animales , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Células Endoteliales de la Vena Umbilical Humana , Humanos , Imagen por Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Persona de Mediana Edad , Trasplante de Neoplasias , Análisis de Secuencia por Matrices de Oligonucleótidos , Análisis de Secuencia de ARN , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologíaRESUMEN
PURPOSE: Previous studies have revealed that PHLDB1 single-nucleotide polymorphisms (SNPs) are associated with glioma risk. Nonetheless, the association between PHLDB1 SNPs and the risk of pituitary adenoma has not been studied. The present study evaluated the association of PHLDB1 SNPs with the risk of pituitary adenomas. METHODS: We genotyped 27 PHLDB1 tagging and exon SNPs in a case-control study that included 148 patients who got a diagnosis of nonfunctional pituitary adenoma (NFPA) and 375 normal controls within the Korean population. Statistical analyses of the association between PHLDB1 SNPs and the NFPA risk were conducted using logistic regression. RESULTS: We detected an association between a PHLDB1 SNP and the risk of NFPA in the Korean population. Rs67307131 in intron 2 was significantly associated with NFPA (odds ratio [OR] = 2.15, 95% confidence interval [CI] 1.44-3.20; P = 0.0002 in the dominant model). In the referent analysis, a higher OR and stronger association (lower P value) were observed among patients with the "C/T" genotype (OR = 2.39, 95% CI 1.60-3.58; P = 0.00002). In a functional analysis with a SNP annotation tool, this SNP was predicted to be a CpG site and copy number variant; these properties are associated with susceptibility to diseases. CONCLUSIONS: Our findings suggest that genetic variation of PHLDB1 may be associated with the risk of NFPA. This is the first report of an association between PHLDB1 variants and NFPA. Further research is needed to confirm the impact of this SNP on NFPA susceptibility.
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Adenoma/genética , Predisposición Genética a la Enfermedad , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas del Tejido Nervioso/genética , Neoplasias Hipofisarias/genética , Polimorfismo de Nucleótido Simple , Estudios de Casos y Controles , Simulación por Computador , Islas de CpG , Variaciones en el Número de Copia de ADN , Femenino , Haplotipos , Humanos , Intrones , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Modelos GenéticosRESUMEN
OBJECTIVE: Precise knowledge regarding the mechanical stress applied to the intervertebral disc following each individual spine motion enables physicians and patients to understand how people with discogenic back pain should be guided in their exercises and which spine motions to specifically avoid. We created an intervertebral disc degeneration model and conducted a finite element (FE) analysis of loaded stresses following each spinal posture or motion. METHODS: A 3-dimensional FE model of intervertebral disc degeneration at L4-5 was constructed. The intervertebral disc degeneration model was created according to the modified Dallas discogram scale. The von Mises stress and range of motion (ROM) regarding the intervertebral discs and the endplates were analyzed. RESULTS: We observed that mechanical stresses loaded onto the intervertebral discs were similar during flexion, extension, and lateral bending, which were greater than those occurring during torsion. Based on the comparison among the grades divided by the modified Dallas discogram scale, the mechanical stress during extension was greater in grades 3-5 than it was during the others. During extension, the mechanical stress loaded onto the intervertebral disc and endplate was greatest in the posterior portion. Mechanical stresses loaded onto the intervertebral disc were greater in grades 3-5 compared to those in grades 0-2. CONCLUSION: Our findings suggest that it might be beneficial for patients experiencing discogenic back pain to maintain a neutral posture in their lumbar spine when engaging in daily activities and exercises, especially those suffering from significant intravertebral disc degeneration.
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OBJECTIVE: The risks of nonunion and subsidence are high in patients with bone density loss undergoing spinal fusion surgery. The internal application of recombinant human bone morphogenic protein 2 (rhBMP-2) in an interbody cage improves spinal fusion; however, related complications have been reported. Denosumab, a human monoclonal antibody targeting the receptor activator of nuclear factor kappa B ligand (RANKL), hinders osteoblast differentiation and function. Therefore, this study aimed to observe the combined effect of the local application of rhBMP-2 in a lumbar cage and systemic RANKL inhibition on postoperative spinal fusion in patients with bone density loss undergoing posterior lumbar interbody fusion (PLIF). METHODS: This retrospective observational study included 251 consecutive patients with spinal stenosis who underwent PLIF at a single center between 2017 and 2021. Clinical outcomes were assessed, and radiographic evaluations included lumbar flexion, extension, range of motion, and subsidence. Statistical analyses were conducted to identify the combined effect of the treatment and the subsidence and spinal fusion status. RESULTS: One hundred patients were included in the final analysis. Denosumab treatment significantly reduced the rate of osteolysis (p = 0.013). When denosumab was administered in combination with rhBMP-2, the fusion status remained similar; however, the incidences of postoperative osteolysis and postoperative oozing day decreased. CONCLUSION: The combined use of rhBMP-2 and RANKL inhibition in patients with bone density loss can enhance bone formation after PLIF with fewer complications than rhBMP-2 alone.
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OBJECTIVE: Although chronic exposure to air pollution is associated with an increased risk of dementia in normal elderlies, the effect of chronic exposure to air pollution on the rates of cognitive decline in Alzheimer's disease (AD) has not been elucidated. METHODS: In this longitudinal study, a total of 269 patients with mild cognitive impairment or early dementia due to AD with the evidence of brain ß-amyloid deposition were followed-up for a mean period of 4 years. Five-year normalized hourly cumulative exposure value of each air pollutant, such as carbon monoxide (CO), nitrogen dioxide (NO2 ), sulfur dioxide (SO2 ), and particulate matter (PM2.5 and PM10 ), was computed based on nationwide air pollution database. The effects of chronic exposure to air pollution on longitudinal cognitive decline rate were evaluated using linear mixed models. RESULTS: Higher chronic exposure to SO2 was associated with a faster decline in memory score, whereas chronic exposure to CO, NO2 , and PM10 were not associated with the rate of cognitive decline. Higher chronic exposure to PM2.5 was associated with a faster decline in visuospatial score in apolipoprotein E ε4 carriers. These effects remained significant even after adjusting for potential confounders. INTERPRETATION: Our findings suggest that chronic exposure to SO2 and PM2.5 is associated with faster clinical progression in AD.
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Contaminantes Atmosféricos , Contaminación del Aire , Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Estudios Longitudinales , Dióxido de Nitrógeno/efectos adversos , Enfermedad de Alzheimer/etiología , Contaminación del Aire/efectos adversos , Contaminantes Atmosféricos/efectos adversos , Contaminantes Atmosféricos/análisis , Material Particulado/efectos adversos , Disfunción Cognitiva/etiologíaRESUMEN
PURPOSE: Glioblastoma (GBM) is one of the most lethal human tumors with a highly infiltrative phenotype. Our previous studies showed that GBM originates in the subventricular zone, and that tumor-derived mesenchymal stem-like cells (tMSLCs) promote the invasiveness of GBM tumorspheres (TSs). Here, we extend these studies in terms of ventricles using several types of GBM patient-derived cells. MATERIALS AND METHODS: The invasiveness of GBM TSs and ventricle spheres (VSs) were quantified via collagen-based 3D invasion assays. Gene expression profiles were obtained from microarray data. A mouse orthotopic xenograft model was used for in vivo experiments. RESULTS: After molecular and functional characterization of ventricle-derived mesenchymal stem-like cells (vMSLCs), we investigated the effects of these cells on the invasiveness of GBM TSs. We found that vMSLC-conditioned media (CM) significantly accelerated the invasiveness of GBM TSs and VSs, compared to the control and even tMSLC-CM. Transcriptome analyses revealed that vMSLC secreted significantly higher levels of several invasiveness-associated cytokines. Moreover, differentially expressed genes between vMSLCs and tMSLCs were enriched for migration, adhesion, and chemotaxis-related gene sets, providing a mechanistic basis for vMSLC-induced invasion of GBM TSs. In vivo experiments using a mouse orthotopic xenograft model confirmed vMSLC-induced increases in the invasiveness of GBM TSs. CONCLUSION: Although vMSLCs are non-tumorigenic, this study adds to our understanding of how GBM cells acquire infiltrative features by vMSLCs, which are present in the region where GBM genesis originates.
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Neoplasias Encefálicas , Glioblastoma , Animales , Humanos , Glioblastoma/genética , Glioblastoma/patología , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Invasividad Neoplásica/genética , Modelos Animales de Enfermedad , Línea Celular Tumoral , Células Madre Neoplásicas/metabolismoRESUMEN
OBJECTIVE: The objective of this study was to evaluate the accuracy of pedicle screw placement in patients undergoing percutaneous pedicle screw fixation with robotic guidance, using a newly developed 3-dimensional quantitative measurement system. The study also aimed to assess the clinical feasibility of the robotic system in the field of spinal surgery. METHODS: A total of 113 patients underwent pedicle screw insertion using the CUVIS-spine pedicle screw guide system (CUREXO Inc.). Intraoperative O-arm images were obtained, and screw insertion pathways were planned accordingly. Image registration was performed using paired-point registration and iterative closest point methods. The accuracy of the robotic-guided pedicle screw insertion was assessed using 3-dimensional offset calculation and the Gertzbein-Robbins system (GRS). RESULTS: A total of 448 screws were inserted in the 113 patients. The image registration success rate was 95.16%. The average error of entry offset was 2.86 mm, target offset was 2.48 mm, depth offset was 1.99 mm, and angular offset was 3.07°. According to the GRS grading system, 88.39% of the screws were classified as grade A, 9.60% as grade B, 1.56% as grade C, 0.22% as grade D, and 0.22% as grade E. Clinically acceptable screws (GRS grade A or B) accounted for 97.54% of the total, with no reported neurologic complications. CONCLUSION: Our study demonstrated that pedicle screw insertion using the novel robot-assisted navigation method is both accurate and safe. Further prospective studies are necessary to explore the potential benefits of this robot-assisted technique in comparison to conventional approaches.
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Gliomas are the most common primary tumors in the brain and spinal cord. In previous GWASs, SNPs in epidermal growth factor receptor (EGFR) have been reported as risk loci for gliomas. However, EGFR variants associated with gliomas in the Korean population remain unstudied. This study explored the association of EGFR SNPs with the risk of glioma. We genotyped 13 EGFR exon SNPs in a case-control study that included 324 Korean patients diagnosed with glioma and 480 population-based controls. Statistical analyses of the association between EGFR SNPs and glioma risk were conducted using logistic regression. Both stepwise analysis and conditional logistic analysis were performed to identify independent associations among genotyped variants. We confirmed that two SNPs (rs2227983, rs1050171) were significantly associated with glioma (rs2227983: odds ratio = 1.42, Pcorr = 0.009; rs1050171: odds ratio = 1.68, Pcorr = 0.005). Additionally, the stepwise analysis and conditional logistic analysis indicated that both SNPs created variants with independent genetic effects. This study is the first to show evidence that functional variants of EGFR, namely, rs2227983 (K521R) and rs1050171 (Q787Q), are associated with an increased risk of glioma in the Korean population. Future work should confirm the functional association between EGFR variants and glioma.
Asunto(s)
Neoplasias Encefálicas , Glioma , Humanos , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Factores de Riesgo , Glioma/epidemiología , Glioma/genética , Polimorfismo de Nucleótido Simple , Receptores ErbB/genética , República de Corea/epidemiología , Neoplasias Encefálicas/epidemiología , Neoplasias Encefálicas/genéticaRESUMEN
Despite aggressive clinical treatment, recurrence of glioblastoma multiforme (GBM) is unavoidable, and the clinical outcome is still poor. A convincing explanation is the phenotypic transition of GBM cells upon aggressive treatment such as radiotherapy. However, the microenvironmental factors contributing to GBM recurrence after treatment remain unexplored. Here, it is shown that radiation-treated GBM cells produce soluble intercellular adhesion molecule-1 (sICAM-1) which stimulates the infiltration of macrophages, consequently enriching the tumor microenvironment with inflammatory macrophages. Acting as a paracrine factor, tumor-derived sICAM-1 induces macrophages to secrete wingless-type MMTV integration site family, member 3A (WNT3A), which promotes a mesenchymal shift of GBM cells. In addition, blockade of either sICAM-1 or WNT3A diminishes the harmful effect of radiation on tumor progression. Collectively, the findings indicate that cellular crosstalk between GBM and macrophage through sICAM-1-WNT3A oncogenic route is involved in the mesenchymal shift of GBM cells after radiation, and suggest that radiotherapy combined with sICAM-1 targeted inhibition would improve the clinical outcome of GBM patients.
Asunto(s)
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Molécula 1 de Adhesión Intercelular/genética , Molécula 1 de Adhesión Intercelular/metabolismo , Macrófagos/metabolismo , Mesodermo/metabolismo , Animales , Neoplasias Encefálicas/genética , Modelos Animales de Enfermedad , Glioblastoma/genética , Humanos , Masculino , Ratones , Ratones DesnudosRESUMEN
Patient-specific cancer therapies can evolve by vitalizing the mother tissue-like cancer niche, cellular profile, genetic signature, and drug responsiveness. This evolution has enabled the elucidation of a key mechanism along with development of the mechanism-driven therapy. After surgical treatment, glioblastoma (GBM) patients require prompt therapy within 14 days in a patient-specific manner. Hence, this study approaches direct culture of GBM patient tissue (1 mm diameter) in a microchannel network chip. Cancer vasculature-mimetic perfusion can support the preservation of the mother tissue-like characteristic signatures and microenvironment. When temozolomide and radiation are administered within 1 day, the responsiveness of the tissue in the chip reflected the clinical outcomes, thereby overcoming the time-consuming process of cell and organoid culture. When the tissue chip culture is continued, the intact GBM signature gets lost, and the outward migration of stem cells from the tissue origin increases, indicating a leaving-home effect on the family dismantle. Nanovesicle production using GBM stem cells enables self-chasing of the cells that escape the temozolomide effect owing to quiescence. The anti-PTPRZ1 peptide display and temozolomide loading to nanovesicles awakes cancer stem cells from the quiescent stage to death. This study suggests a GBM clinic-driven avatar platform and mechanism-learned nanotherapy for translation.
Asunto(s)
Neoplasias Encefálicas , Glioblastoma , Nanomedicina , Humanos , Neoplasias Encefálicas/terapia , Línea Celular Tumoral , Glioblastoma/terapia , Células Madre Neoplásicas , Temozolomida/farmacología , Microambiente TumoralRESUMEN
PURPOSE: A critical indicator of the overall survival of patients with high-grade glioma is the successful isolation of tumor mesenchymal stem-like cells (tMSLCs), which play important roles in glioma progression. However, attempts to isolate tMSLCs from surgical specimens have not always been successful, and the reasons for this remain unclear. Considering that the amount of surgical high-grade glioma specimens varies, we hypothesized that larger surgical specimens would be better for tMSLC isolation. MATERIALS AND METHODS: We assessed 51 fresh, high-grade glioma specimens and divided them into two groups according to the success or failure of tMSLC isolation. The success of tMSLC isolation was confirmed by plastic adherence, presenting antigens, tri-lineage differentiation, and non-tumorigenicity. Differences in characteristics between the two groups were tested using independent two sample t-tests, chi-square tests, or Kaplan-Meier survival analysis. RESULTS: The mean specimen weights of the groups differed from each other (tMSLC-negative group: 469.9±341.9 mg, tMSLC positive group: 546.7±618.9 mg), but the difference was not statistically significant. The optimal cut-off value of specimen weight was 180 mg, and the area under the curve value was 0.599. CONCLUSION: Our results suggested a minimum criterion for specimen collection, and found that the specimen amount was not deeply related to tMSLC detection. Collectively, our findings imply that the ability to isolate tMSLCs is determined by factors other than the specimen amount.