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1.
Cell Biochem Funct ; 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31833081

RESUMO

Glioblastoma (GBM) is the most malignant and aggressive glioma, which has a very poor prognosis. Temozolomide (TMZ) is still a first-line treatment, but resistance is inevitable even in MGMT-deficient glioblastoma cells. The aims of this study were to comprehend the effect of TMZ on nucleus and the underlying mechanism of acquired TMZ resistance in MGMT-deficient GBM. We show the changes of nuclear proteome in the MGMT-deficient GBM U87 cells treated with TMZ for 1 week. Label-free-based quantitative proteomics were used to investigate nuclear protein abundance change. Subsequently, gene ontology function annotation, KEGG pathway analysis, protein-protein interaction (PPI) network construction analysis of DAPs, and immunofluorescence were applied to validate the quality of proteomics. In total, 457 (455 gene products) significant DAPs were identified, of which 327 were up-regulated and 128 were down-regulated. Bioinformatics analysis uncovered RAD50, MRE11, UBR5, MSH2, MSH6, DDB1, DDB2, RPA1, RBX1, CUL4A, and CUL4B mainly enriched in DNA damage repair related pathway and constituted a protein-protein interaction network. Ribosomal proteins were down-regulated. Cells were in a stress-responsive state, while the entire metabolic level was lowered. SIGNIFICANCE OF THE STUDY: In U87 cell treated with TMZ for 1 week, which resulted in DNA damage, we found various proteins dysregulated in the nucleus. Some proteins related to the DNA damage repair pathway were up-regulated, and there was a strong interaction. We believe this is the potential clues of chemotherapy resistance in tumour cells. These proteins can be used as indicators of tumour resistance screening in the future.

2.
Metabolism ; 101: 153998, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31666193

RESUMO

BACKGROUND: The incidence of growth hormone deficiency (GHD) in adamantinomatous craniopharyngioma (aCP) is significantly higher than in other sellar region tumors, but the possible mechanism is still elusive. A high level of inflammatory responses is another feature of aCP. We investigated the internal connection between interleukin-1α (IL-1α) and GHD, while focusing on its biological activities in pituitary fibrosis. MATERIALS AND METHODS: To diagnosis of GHD, the Body Mass Index (BMI), Insulin Like Growth Factor-1(IGF-1) and peak growth hormone (GH) values after insulin stimulation test of 15 aCP patients were recorded. Histological staining was performed on the aCP samples. Levels of 9 proinflammatory cytokines in tumor tissue and cell supernatant were detected using Millipore bead arrays. The effect of IL-1α on GH secretion was evaluated in vivo and in vitro. Western blot, qRT-PCR and cell functional assays were used to explore the potential mechanism through which IL-1α acts on GH secretion. The stereotactic ALZET osmotic pump technique was used to simulate aCP secretion of proinflammatory cytokines in rats. Recombinant IL-1α (rrIL-1α) and conditioned media (CM) prepared from the supernatant of aCP cells was infused directly into the intra-sellar at a rate of 1 µl/h over 28 days, and then the effects of IL-1α treatment on pathological changes of pituitary gland and GH secretion were measured. To further confirm whether IL-1α affects GH secretion through IL-1R1, an IL-1R1 blocker (IL-1R1a, 10 mg/kg body weight, once daily) was administered subcutaneously from the first day until day 28. RESULTS: There was a significant positive correlation between pituitary fibrosis and GHD (rS = 0.756, P = 0.001). A number of cytokines, in particular IL-1α, interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1), were elevated in tumor tissue and cell supernatant. Only IL-1α showed a significant difference between the GHD group and the No-GHD group (P < 0.001, F = 6.251 in tumor tissue; P = 0.003, F = 1.529 in cell supernatant). IL-1α significantly reduced GH secretion in coculture of GH3 and pericytes. The activation of pericytes induced by IL-1α was mediated by the IL-1R1 signaling pathway. In vivo, IL-1α induces pituitary fibrosis, further leading to a decreased level of GH. This pathological change was antagonized by IL-1R1a. CONCLUSION: This study found that the cross talk between aCP cells and stroma cells in the pituitary, i.e. pericytes, is an essential factor in the formation of GHD, and we propose that neutralization of IL-1α signaling might be a potential therapy for GHD in aCP.

3.
BMC Med Genomics ; 12(1): 165, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31729991

RESUMO

BACKGROUND: Previously developed classifications of glioma have provided enormous advantages for the diagnosis and treatment of glioma. Although the role of alternative splicing (AS) in cancer, especially in glioma, has been validated, a comprehensive analysis of AS in glioma has not yet been conducted. In this study, we aimed at classifying glioma based on prognostic AS. METHODS: Using the TCGA glioblastoma (GBM) and low-grade glioma (LGG) datasets, we analyzed prognostic splicing events. Consensus clustering analysis was conducted to classified glioma samples and correlation analysis was conducted to characterize regulatory network of splicing factors and splicing events. RESULTS: We analyzed prognostic splicing events and proposed novel splicing classifications across pan-glioma samples (labeled pST1-7) and across GBM samples (labeled ST1-3). Distinct splicing profiles between GBM and LGG were observed, and the primary discriminator for the pan-glioma splicing classification was tumor grade. Subtype-specific splicing events were identified; one example is AS of zinc finger proteins, which is involved in glioma prognosis. Furthermore, correlation analysis of splicing factors and splicing events identified SNRPB and CELF2 as hub splicing factors that upregulated and downregulated oncogenic AS, respectively. CONCLUSION: A comprehensive analysis of AS in glioma was conducted in this study, shedding new light on glioma heterogeneity and providing new insights into glioma diagnosis and treatment.

4.
J Biophotonics ; : e201900196, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31743584

RESUMO

Heterogeneity is regarded as the major factor leading to the poor outcomes of glioblastoma (GBM) patients. However, conventional two-dimensional (2D) analysis methods, such as immunohistochemistry and immunofluorescence, have limited capacity to reveal GBM spatial heterogeneity. Thus, we sought to develop an effective analysis strategy to increase the understanding of GBM spatial heterogeneity. Here, 2D and three-dimensional (3D) analysis methods were compared for the examination of cell morphology, cell distribution and large intact structures, and both types of methods were employed to dissect GBM spatial heterogeneity. The results showed that 2D assays showed only cross-sections of specimens but provided a full view. To visualize intact GBM specimens in 3D without sectioning, the optical tissue clearing methods CUBIC and iDISCO+ were used to clear opaque specimens so that they would become more transparent, after which the specimens were imaged with a two-photon microscope. The 3D analysis methods showed specimens at a large spatial scale at cell-level resolution and had overwhelming advantages in comparison to the 2D methods. Furthermore, in 3D, heterogeneity in terms of cell stemness, the microvasculature, and immune cell infiltration within GBM was comprehensively observed and analysed. Overall, we propose that 2D and 3D analysis methods should be combined to provide much greater detail to increase the understanding of GBM spatial heterogeneity.

5.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(9): 1099-1106, 2019 Sep 30.
Artigo em Chinês | MEDLINE | ID: mdl-31640965

RESUMO

OBJECTIVE: To investigate the mechanism by which doublecortin promotes the recovery of cytoskeleton in arginine vasopressin (AVP) neurons in rats with electrical lesions of the pituitary stalk (PEL). METHODS: Thirty-two SD rats were randomized into PEL group with electrical lesions of the pituitary stalk through the floor of the skull base (n=25) and sham operation group (n=7), and the daily water consumption (DWC), daily urine volume (DUV) and urine specific gravity (USG) of the rats were recorded. Four rats on day 1 and 7 rats on each of days 3, 7 and 14 after PEL as well as the sham-operated rats were sacrificed for detection of the expressions of ß-Tubulin (Tuj1), doublecortin and caspase- 3 in the AVP neurons of the supraoptic nucleus using immunofluorescence assay and Western blotting. RESULTS: After PEL, the rats exhibited a typical triphasic pattern of diabetes insipidus, with the postoperative days 1-2 as the phase one, days 3-5 as the phase two, and days 6-14 as the phase three. Immunofluorescent results indicated the repair of the AVP neurons evidenced by significantly increased doublecortin expressions in the AVP neurons following PEL; similarly, the expression of Tuj1 also increased progressively after PEL, reaching the peak level on day 7 after PEL. The apoptotic rates of the AVP neurons exhibited a reverse pattern of variation, peaking on postoperative day 3 followed by progressive reduction till day 14. Western blotting showed that the expressions of c-Jun and p-c-Jun were up-regulated significantly on day 3 (P < 0.05) and 7 (P < 0.01) after PEL, while an upregulated p-JNK expression was detected only on day 3 (P < 0.05), as was consistent with the time-courses of neuronal recovery and apoptosis after PEL. CONCLUSIONS: JNK/c-Jun pathway is activated after PEL to induce apoptosis of AVP neurons in the acute phase and to promote the repair of neuronal cytoskeleton by up-regulation of doublecortin and Tuj1 expressions.


Assuntos
Arginina Vasopressina/farmacologia , Citoesqueleto/metabolismo , Sistema de Sinalização das MAP Quinases , Neurônios/citologia , Hipófise/lesões , Regeneração , Animais , Apoptose , Hipófise/citologia , Proteínas Proto-Oncogênicas c-jun/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Tubulina (Proteína)/metabolismo
6.
J Vis Exp ; (151)2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31545320

RESUMO

3D printing has been widely applied in the medical field since the 1980s, especially in surgery, such as preoperative simulation, anatomical learning and surgical training. This raises the possibility of using 3D printing to construct a neurosurgical implant. Our previous works took the construction of the burr hole ring as an example, described the process of using softwares like computer aided design (CAD), Pro/Engineer (Pro/E) and 3D printer to construct physical products. That is, a total of three steps are required, the drawing of 2D-image, the construction of 3D-image of burr hole ring, and using a 3D printer to print the physical model of burr hole ring. This protocol shows that the burr hole ring made of carbon fiber can be rapidly and accurately molded by 3D printing. It indicated that both CAD and Pro/E softwares can be used to construct the burr hole ring via integrating with the clinical imaging data and further applied 3D printing to make the individual consumables.

7.
Aging (Albany NY) ; 11(15): 5300-5318, 2019 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-31386624

RESUMO

Accumulating evidence has implied that microRNAs (miRNAs) are implicated in glioma progression, and genetically engineered mesenchymal stem cells can help to inhibit tumor growth of glioma. Herein we hypothesized that miR-199a could be delivered by mesenchymal stem cells to glioma cells through exosomes and thus prevent the glioma development by down-regulating ArfGAP with GTPase domain, ankyrin repeat and PH domain 2 (AGAP2). The expression pattern of miR-199a and AGAP2 was characterized in glioma tissues and cells using RNA polymerase chain reaction quantification, immunohistochemical staining and Western blot assays. Mesenchymal stem cells transfected with miR-199a mimic or their derived exosomes were co-cultured with U251 cells. The biological behaviors as well as chemosensitivity of U251 cells were assessed to explore the involvement of miR-199a/AGAP2 in glioma. MiR-199a was poorly expressed in glioma tissue and cells while AGAP2 was highly expressed. Mesenchymal stem cells delivered miR-199a to the glioma cells via the exosomes, which resulted in the suppression of the proliferation, invasion and migration of glioma cells. Besides, mesenchymal stem cells over-expressing miR-199a enhanced the chemosensitivity to temozolomide and inhibited the tumor growth in vivo. Taken together, mesenchymal stem cell-derived exosomal miR-199a can inhibit the progression of glioma by down-regulating AGAP2.

8.
J Neurosurg ; : 1-11, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31470408

RESUMO

OBJECTIVE: Nuclear ß-catenin, a hallmark of active canonical Wnt signaling, can be histologically detected in a subset of cells and cell clusters in up to 94% of adamantinomatous craniopharyngioma (ACP) samples. However, it is unclear whether nuclear ß-catenin-containing cells within human ACPs possess the characteristics of tumor stem cells, and it is unknown what role these cells have in ACP. METHODS: Primary ACP cells were cultured from 12 human ACP samples. Adamantinomatous CP stem cell-like cells (CSLCs) showing CD44 positivity were isolated from the cultured primary ACP cells by performing magnetic-activated cell sorting. The tumor sphere formation, cell cycle distribution, stemness marker expression, and multidifferentiation potential of the CD44- cells and the CSLCs were analyzed. RESULTS: Compared with the CD44- cells, the cultured human CSLCs formed tumor spheres and expressed CD44 and CD133; moreover, these cells demonstrated nuclear translocation of ß-catenin. In addition, the CSLCs demonstrated osteogenic and adipogenic differentiation capacities compared with the CD44- cells. The CSLCs also displayed the capacity for tumor initiation in human-mouse xenografts. CONCLUSIONS: These results indicate that CSLCs play an important role in ACP development, calcification, and cystic degeneration.

9.
Brain ; 142(8): 2352-2366, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31347685

RESUMO

The acquisition of temozolomide resistance is a major clinical challenge for glioblastoma treatment. Chemoresistance in glioblastoma is largely attributed to repair of temozolomide-induced DNA lesions by O6-methylguanine-DNA methyltransferase (MGMT). However, some MGMT-deficient glioblastomas are still resistant to temozolomide, and the underlying molecular mechanisms remain unclear. We found that DYNC2H1 (DHC2) was expressed more in MGMT-deficient recurrent glioblastoma specimens and its expression strongly correlated to poor progression-free survival in MGMT promotor methylated glioblastoma patients. Furthermore, silencing DHC2, both in vitro and in vivo, enhanced temozolomide-induced DNA damage and significantly improved the efficiency of temozolomide treatment in MGMT-deficient glioblastoma. Using a combination of subcellular proteomics and in vitro analyses, we showed that DHC2 was involved in nuclear localization of the DNA repair proteins, namely XPC and CBX5, and knockdown of either XPC or CBX5 resulted in increased temozolomide-induced DNA damage. In summary, we identified the nuclear transportation of DNA repair proteins by DHC2 as a critical regulator of acquired temozolomide resistance in MGMT-deficient glioblastoma. Our study offers novel insights for improving therapeutic management of MGMT-deficient glioblastoma.

10.
Cancer Med ; 8(10): 4527-4535, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31240876

RESUMO

BACKGROUND: Glioma-related epilepsy (GRE) is defined as symptomatic epileptic seizures secondary to gliomas, it brings both heavy financial and psychosocial burdens to patients with diffuse glioma and significantly decreases their quality of life. To date, there have been no clinical guidelines that provide recommendations for the optimal diagnostic and therapeutic procedures for GRE patients. METHODS: In March 2017, the Joint Task Force for GRE of China Association Against Epilepsy and Society for Neuro-Oncology of China launched the guideline committee for the diagnosis and treatment of GRE. The guideline committee conducted a comprehensive review of relevant domestic and international literatures that were evaluated and graded based on the Oxford Centre for Evidence-Based Medicine Levels of Evidence, and then held three consensus meetings to discuss relevant recommendations. The recommendations were eventually given according to those relevant literatures, together with the experiences in the diagnosis and treatment of over 3000 GRE cases from 24 tertiary level hospitals that specialize in clinical research of epilepsy, glioma, and GRE in China. RESULTS: The manuscript presented the current standard recommendations for the diagnostic and therapeutic procedures of GRE. CONCLUSIONS: The current work will provide a framework and assurance for the diagnosis and treatment strategy of GRE to reduce complications and costs caused by unnecessary treatment. Additionally, it can serve as a reference for all professionals involved in the management of patients with GRE.

11.
Theranostics ; 9(7): 1909-1922, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31037147

RESUMO

Rationale: Glioblastoma (GBM) is the most common and aggressive brain tumor, characterized by its propensity to invade the surrounding brain parenchyma. The effect of extracellular high-mobility group box 1 (HMGB1) protein on glioblastoma (GBM) progression is still controversial. p62 is overexpressed in glioma cells, and has been associated with the malignant features and poor prognosis of GBM patients. Hence, this study aimed to clarify the role of p62 in HMGB1-induced epithelial-mesenchymal transition (EMT) of GBM both in vitro and in vivo. Methods: Immunoblotting, immunofluorescence and qRT-PCR were performed to evaluate EMT progression in both human GBM cell line and primary GBM cells. Transwell and wound healing assays were used to assess the invasion and migration of GBM cells. shRNA technique was used to investigate the role of p62 in HMGB1-induced EMT both in vitro and in vivo orthotopic tumor model. Co-immunoprecipitation assay was used to reveal the interaction between p62 and GSK-3ß (glycogen synthase kinase 3 beta). Immunohistochemistry was performed to detect the expression levels of proteins in human GBM tissues. Results: In this study, GBM cells treated with recombinant human HMGB1 (rhHMGB1) underwent spontaneous EMT through GSK-3ß/Snail signaling pathway. In addition, our study revealed that rhHMGB1-induced EMT of GBM cells was accompanied by p62 overexpression, which was mediated by the activation of TLR4-p38-Nrf2 signaling pathway. Moreover, the results demonstrated that p62 knockdown impaired rhHMGB1-induced EMT both in vitro and in vivo. Subsequent mechanistic investigations showed that p62 served as a shuttling factor for the interaction of GSK-3ß with proteasome, and ultimately activated GSK-3ß/Snail signaling pathway by augmenting the degradation of GSK-3ß. Furthermore, immunohistochemistry analysis revealed a significant inverse correlation between p62 and GSK-3ß, and a combination of the both might serve as a more powerful predictor of poor survival in GBM patients. Conclusions: This study suggests that p62 is an effector for HMGB1-induced EMT, and may represent a novel therapeutic target in GBM.

12.
Mol Med Rep ; 19(6): 5406-5416, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059035

RESUMO

Long noncoding RNAs (lncRNAs) are a novel class of gene regulators involved in tumor biogenesis. Glioblastoma is the most common and malignant type of brain tumor. The function and prognostic significance of lncRNAs in glioblastoma remain unclear. In the present study, updated gene annotations were adopted to investigate lncRNA expression profiles in publicly available glioma microarray datasets from the Gene Expression Omnibus and the Repository for Molecular Brain Neoplasia Data. In a training set of 108 samples of glioblastoma, using univariate Cox regression analysis with a permutation P<0.005, four lncRNAs, including insulin­like growth factor binding protein 7­antisense 1 (IGFBP7­AS1), were significantly associated with patient overall survival. These four lncRNAs were integrated as an expression­based molecular signature to divide patients in the training set into high­risk and low­risk subgroups, with distinct survival rates (hazard ratio, 2.72; 95% CI, 1.71­4.31; P<0.001). The prognostic value of the lncRNA signature was confirmed in two additional datasets comprising a total of 147 samples from patients with glioblastoma. The prognostic value of this signature was independent of age and Karnofsky performance status. This signature was also able to predict different outcomes in cases of glioblastoma associated with an isocitrate dehydrogenase 1 mutation. Further bioinformatics analyses revealed that 'epithelial­mesenchymal transition' and 'p53 pathway' gene sets were enriched in glioblastoma samples with higher IGFBP7­AS1 expression. Furthermore, in vitro experiments demonstrated that knockdown of IGFBP7­AS1 inhibited the viability, migration and invasion of U87 and U251 glioma cells. In conclusion, the present study identified a lncRNA signature able to predict glioblastoma outcomes, and provided novel information regarding the role of IGFBP7­AS1 in glioma development.


Assuntos
Neoplasias Encefálicas/patologia , Glioblastoma/patologia , RNA Longo não Codificante/metabolismo , Transcriptoma , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Linhagem Celular Tumoral , Movimento Celular , Sobrevivência Celular , Feminino , Glioblastoma/genética , Glioblastoma/mortalidade , Humanos , Estimativa de Kaplan-Meier , Avaliação de Estado de Karnofsky , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Modelos de Riscos Proporcionais , Interferência de RNA , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/genética , RNA Interferente Pequeno/metabolismo
13.
Tissue Cell ; 58: 93-98, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31133252

RESUMO

This study aimed to propose a simple and practical method for culturing primary rat somatotropic cells in vitro free of pericytes contamination. Rat adenohypophyses were randomly divided into two groups. An improved method was used in group A (digesting adenohypophysis with 0.25% trypsin-EDTA, followed by removing pericytes by double filtration and using serum-free medium for culturing somatotropic cells). The traditional method was used in group B (digesting adenohypophysis with 0.35% collagenase, using serum medium for culturing somatotropic cells, and removing pericytes by changing the culture dish). The numbers and viability of somatotropic cells were higher in group A than in group B after 6 days. GH secretion of somatotropic cells was also higher in group A than in group B. Besides, the pericytes grew rapidly only in group B after 3 days. α-SMA, type I collagen, and type III collagen had weaker expression in group A. Also, the viability of pericytes decreased in group A. The improved method could solve the problem of pericytes contamination, and the culture of primary rat somatotropic cells in vitro was successful. This method can be used for other primary cultures with pericytes contamination.


Assuntos
Técnicas de Cultura de Células/métodos , Separação Celular , Somatotrofos/citologia , Animais , Sobrevivência Celular , Meios de Cultura Livres de Soro/química , Meios de Cultura Livres de Soro/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Somatotrofos/metabolismo
14.
J Craniofac Surg ; 30(7): 1942-1945, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30908437

RESUMO

OBJECTIVE: To evaluate the predictive power of the brain stem reflexes (BSRs) for minimally conscious state in unconscious patients after traumatic brain injury. MATERIALS AND METHODS: A total of 120 patients with duration of unconsciousness were enrolled in this study. BSRs were recorded 14 days after Traumatic brain injury, and classified into 3 grades. Predictors including BSRs, age, sex, Glasgow Coma Scale (GCS), and cause of injury were also analyzed, respectively. The outcome was divided into 2 groups including unconscious group and minimally conscious state (MCS) group. RESULTS: Seventy-two of 120 were minimally conscious and 48 of 120 were unconscious at 6 months from the onset of injury. The BSRs outmatched the predictive accuracy of the GCS for outcome (AUROC, 0.853; 95% confidence interval, 0.753-0.953; and AUROC, 0.655; 95% confidence interval, 0.512-0.799, respectively). BSRs grade (P < 0.001) and GCS (P < 0.05) were significantly associated with the outcome. The accuracy of the whole regression model for predicting unconscious and MCS was 91.7% and 79.2%, respectively. CONCLUSION: The BSRs grade shows a significantly higher accuracy for prediction of MCS compared with the GCS. BSRs grade is a simple, yet reliable and stratification tool for early decision making.


Assuntos
Lesões Encefálicas Traumáticas , Tronco Encefálico , Estado Vegetativo Persistente , Adolescente , Adulto , Idoso , Estado de Consciência , Feminino , Escala de Coma de Glasgow , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Inconsciência , Adulto Jovem
15.
Clin Cancer Res ; 25(12): 3602-3616, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30862693

RESUMO

PURPOSE: Glioblastoma, a common malignant intracranial tumor, has the most dismal prognosis. Autophagy was reported to act as a survival-promoting mechanism in gliomas by inducing epithelial-to-mesenchymal transition (EMT). Here, we determined the critical molecules involved in autophagy-induced EMT and elucidated the possible mechanism of chemoradiotherapy resistance and tumor recurrence. EXPERIMENTAL DESIGN: We used isobaric tags for relative and absolute quantitation to identify the critical proteins and pathway mediating EMT via autophagy inducer treatment, and tested the expression of these proteins using tissue microarray of gliomas and clinical glioblastoma samples as well as tissues and cells separated from the core lesion and tumor-peripheral region. Analysis of the Cancer Genome Atlas database and 110 glioblastoma cases revealed the prognostic value of these molecules. The functional role of these critical molecules was further confirmed by in vitro experiments and intracranial xenograft in nude mice. RESULTS: Autophagy inducers significantly upregulated the expression of HERC3, which promotes ubiquitination-mediated degradation of SMAD7 in an autolysosome-dependent manner. The corresponding increase in p-SMAD2/3 level and TGFß pathway activation finally induced EMT in cell lines and primary glioblastoma cells. Moreover, HERC3 overexpression was observed in pseudo-palisade cells surrounding tumor necrosis and in tumor-adjacent tissue; high HERC3 and low SMAD7 levels predicted poor clinical outcome in glioblastoma; xenograft of nude mice and in vitro experiments confirmed these findings. CONCLUSIONS: Together, our findings reveal the indispensable role of HERC3 in regulating canonical SMAD2/3-dependent TGFß pathway involvement in autophagy-induced EMT, providing insights toward a better understanding of the mechanism of resistance to temozolomide and peripheral recurrence of glioblastoma.

16.
CNS Neurosci Ther ; 25(5): 562-574, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30677238

RESUMO

AIMS: Central diabetes insipidus (CDI), a typical complication caused by pituitary stalk injury, often occurs after surgery, trauma, or tumor compression around hypothalamic structures such as the pituitary stalk and optic chiasma. CDI is linked to decreased arginine vasopressin (AVP) neurons in the hypothalamic supraoptic nucleus and paraventricular nucleus, along with a deficit in circulating AVP and oxytocin. However, little has been elucidated about the changes in AVP neurons in CDI. Hence, our study was designed to understand the role of several pathophysiologic changes such as endoplasmic reticulum (ER) stress and apoptosis of AVP neurons in CDI. METHODS: In a novel pituitary stalk electric lesion (PEL) model to mimic CDI, immunofluorescence and immunoblotting were used to understand the underlying regulatory mechanisms. RESULTS: We reported that in CDI condition, generated by PEL, ER stress induced apoptosis of AVP neurons via activation of the PI3K/Akt and ERK pathways. Furthermore, application of N-acetylcysteine protected hypothalamic AVP neurons from ER stress-induced apoptosis through blocking the PI3K/Akt and ERK pathways. CONCLUSION: Our findings showed that AVP neurons underwent apoptosis induced by ER stress, and ER stress might play a vital role in CDI condition through the PI3K/Akt and ERK pathways.

17.
J BUON ; 24(6): 2458-2464, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31983120

RESUMO

PURPOSE: To investigate whether IDH1 mutation or 2-hydroxyglutarate (2-HG), the oncometabolite produced by IDH mutations, is correlated to epithelial-mesenchymal transition (EMT)-like phenotype in glioma cells, so as to clarify how IDH1 mutation is good prognostic factor while 2-HG, being its oncometabolite, remains unknown. METHODS: U87 and T98 cell lines were treated with 10 mM exogenous 2-HG, and fresh 2-HG was replenished every 2-days intervals. Endogenously heterozygous mutation in IDH1 was generated via lentiviral transduction technology. Morphological analysis, wound healing assay and Boyden migration assay were used to detect the ability of migration of U87 and 2-HG-treated U87 cell lines, and immunoblotting was used to detect the EMT-related transcription factors in glioma cell line. RESULTS: Cellular morphology changed after IDH1 mutation and 2-HG stimulation. The Cell Counting Kit-8 assay, and wound healing assay showed that exogenous 2-HG promotes the proliferation and invasion of glioma cells. Western blot analysis showed that mesenchymal marker ß-Catenin was increased in the exogenous 2-HG-treated and IDH1 mutated U87 cells, while epithelial markers E-cadherin and ZO1 were decreased. CONCLUSIONS: Our study showed some evidence that both IDH1 mutation and 2-HG can lead to EMT-like phenotype and proliferation and migration in glioma cells. EMT-like biomarkers changed in IDH1 mutation cells which generated via lentiviral transduction technology or treated in 2-HG.

18.
J Clin Neurosci ; 58: 229-233, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30454691

RESUMO

BACKGROUND: As the bearing structure of fixation device in deep brain stimulation (DBS), burr hole ring is fixed on the skull and used in conjunction with Stimloc and plastic cap. But in patients with traumatic event, excessive movements are likely to bring strain on the anchoring system, which will finally cause the fixation device to fall off from the skull. METHOD: AutoCAD was used to construct two-dimension (2-D) images for traditional burr hole ring and innovative burr hole ring, respectively. According to the 2-D image, pro/Engineer (Pro/E) will be applied to construct the three-dimension (3-D) geometries. And then, 3-D printing technology was used to build the solid model. These two kinds of burr hole rings were divided into two groups: Innovative group (N = 21) and Traditional group (N = 21). Pull-out strength of these two groups of burr hole rings will be measured by manual tensile force testing machine on the full-size skull model, and the data were transmitted to the notebook in real time for recording and further analyzing. RESULT: The fixation strength of the innovative group is stronger than traditional group, pull-out strength value of traditional group and innovative group were 34.08 ±â€¯1.31 N and 99.73 ±â€¯2.14 N, respectively. (P < 0.001). CONCLUSION: We provide an innovative burr hole ring, which can fix on the burr hole steadily. Moreover, 3-D printing technology may be suitable for personalized and customized medical treatment in the future.


Assuntos
Estimulação Encefálica Profunda/métodos , Eletrodos Implantados , Modelos Anatômicos , Impressão Tridimensional , Crânio/diagnóstico por imagem , Trepanação/métodos , Adulto , Estimulação Encefálica Profunda/instrumentação , Humanos , Imagem Tridimensional/instrumentação , Imagem Tridimensional/métodos , Impressão Tridimensional/instrumentação , Crânio/anatomia & histologia , Crânio/cirurgia , Técnicas Estereotáxicas/instrumentação , Trepanação/instrumentação
19.
J Neuropathol Exp Neurol ; 77(11): 1017-1023, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30239800

RESUMO

The aim of this study was to clarify pathological and anatomical relationships between adamantinomatous craniopharyngiomas (ACP) and their surrounding structures. We previously established a QST classification scheme based on the apparent anatomic origin of the tumors. According to this classification, 13 type Q tumors, 6 type S tumors, and 42 type T ACPs were analyzed. Type Q tumors, which are most likely to involve the pituitary gland, did not invade the area of contact with the adenohypophysis. Instead, tumor invasion was observed in areas where the tumor contacted the neurohypophysis. Type S tumors primarily involved the pituitary stalk; the arachnoid remained present between these tumors and normal structures. Type T tumors were located beneath the basal arachnoid membrane and outside the pia mater. The pia mater was disrupted and finger-like invasions were found in the neural layer of the third ventricle floor along the invasive front. Tumors were never observed to break through the ependymal layer of the third ventricle. The QST classification has important implications for understanding the growth pattern of tumors and can be used to guide surgical procedures.


Assuntos
Craniofaringioma/classificação , Craniofaringioma/patologia , Neoplasias Hipofisárias/classificação , Neoplasias Hipofisárias/patologia , Índice de Gravidade de Doença , Antígeno AC133/metabolismo , Adolescente , Adulto , Idoso , Cateninas/metabolismo , Criança , Pré-Escolar , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Masculino , Pessoa de Meia-Idade , Terceiro Ventrículo/patologia , Adulto Jovem
20.
J Neurol Surg A Cent Eur Neurosurg ; 79(6): 471-478, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29959764

RESUMO

OBJECTIVE: To analyze the long noncoding RNA (lncRNA) expression profile of glioblastoma multiforme (GBM) and identify prognosis-related lncRNAs, as well as their related protein-coding genes and functions. METHOD: The lncRNA expression profiles were obtained by microarray in six samples each of GBM and normal brain tissue. The lncRNAs expressed were significantly different between the two groups and used to detect their associations with patient survival time by downloading the related data from The Cancer Genome Atlas (TCGA). The total RNA-sequencing data of 152 patients diagnosed GBM level 3 with complete clinic information was downloaded. The survival time-dependent lncRNAs were identified by multivariate Cox regression analysis. For the survival time-dependent lncRNAs, we used the Pearson correlation coefficient and z test to search their associated protein-coding genes downloaded from TCGA. Functions of these genes were annotated by the Database for Annotation, Visualization, and Integrated Discovery (DAVID) for gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. RESULTS: More than 1,000 antisense lncRNAs and enhancer lncRNAs were selected for analysis in this study. Data from 152 cases with RNA-seq of GBM level 3 with complete information on GBM were downloaded from the TCGA database. Univariate Cox regression analysis revealed 19 lncRNAs with survival time dependency. These nine lncRNAs were used to construct our survival model via multivariate Cox regression analysis: TP73-AS1, AC078883.3, RP11-944L7.4, HAR1B, RP4-635E18.7, HOTAIR, SAPCD1-AS1, AC104653.1, and RP5-1172N10.2. The nine lncRNAs associated with them were inputted into the DAVID database for gene ontology and KEGG function enrichment analysis. The result showed these genes were enriched with ion binding, transport, cell-cell signaling, plasma membrane parts, and more, and they were mainly related to neuroactive ligand-receptor interaction pathway, calcium signaling pathway, and the mitogen-activated protein kinase signaling pathway. CONCLUSION: The nine lncRNAs were a set of biomarkers for the prognosis of patients with GBM, enabling a more accurate prediction of survival and revealing more biological functions.


Assuntos
Neoplasias Encefálicas/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glioblastoma/metabolismo , RNA Longo não Codificante/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidade , Glioblastoma/genética , Glioblastoma/mortalidade , Humanos , Prognóstico , Estudos Prospectivos , RNA Longo não Codificante/genética , Taxa de Sobrevida
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