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1.
J Ethnopharmacol ; 301: 115855, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36280019

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Myrrh is an aromatic oleo-gum resin extracted from the stem of Commiphora myrrha (Nees) Engl., and has the efficacies to promote blood circulation and remove blood stasis. Myrrh is mainly used for the treatment of chronic diseases including cancer. Guggulsterone, a major active steroid extracted from myrrh, has been found to inhibit cancer cell growth. Glioblastoma is the most common malignancy of central nervous system, and its prognosis remains very poor mainly due to chemotherapeutic resistance. The active status of EGFR/PI3K/Akt and NF-κB signaling in glioblastoma contributed to poor response for chemotherapy, and blocking this signaling with antagonists sensitized glioblastoma cells to chemotherapy. AIM OF THE STUDY: The present study will investigate whether guggulsterone potentiates the anti-glioblastoma efficacy of temozolomide by down-regulating EGFR/PI3K/Akt signaling and NF-κB activation. MATERIALS AND METHODS: Cell viability and proliferation was determined by cell counting Kit-8 and colony formation assays. Cell apoptosis was evaluated by Annexin V/PI and hoechst 33342 staining assays. Molecular techniques such as western blotting and real-time quantitative PCR were used to demonstrate guggulsterone in vitro effect on EGFR/PI3K/Akt signaling and NF-κB activation. Finally, in vivo studies were performed in orthotopic mouse models of glioblastoma. RESULTS: The results demonstrated that guggulsterone enhanced temozolomide-induced growth inhibition and apoptosis in human glioblastoma U251 and U87 cells. Furthermore, the synergistic anti-glioblastoma efficacy between guggulsterone and temozolomide was intimately associated with the inhibition of EGFR/PI3K/Akt signaling and NF-κB activation in U251 and U87 cells. Our in vivo results on orthotopic xenograft models similarly indicated that guggulsterone potentiated temozolomide-induced tumor growth inhibition through suppressing EGFR/PI3K/Akt signaling pathway and NF-кB activity. CONCLUSIONS: The present study suggested that guggulsterone potentiated anti-glioblastoma efficacy of temozolomide through down-regulating EGFR/PI3K/Akt signaling pathway and NF-кB activation.


Assuntos
Glioblastoma , NF-kappa B , Camundongos , Animais , Humanos , Temozolomida/farmacologia , Temozolomida/uso terapêutico , NF-kappa B/metabolismo , Commiphora , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Glioblastoma/tratamento farmacológico , Apoptose , Receptores ErbB/metabolismo , Linhagem Celular Tumoral , Proliferação de Células
2.
J Ethnopharmacol ; 301: 115790, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36208821

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Coriolus versicolor (CV) has been used in traditional Chinese medicine for over 2000 years as a premium medicine for enhancing good health and longevity. The immunomodulatory and anti-cancer effects of polysaccharopeptides (PSP) from cultured CV have been extensively studied; however, the effect and the mechanism of action of other small molecules from CV remain unknown. AIM OF THE STUDY: we aim to examine the immunomodulatory and anti-cancer effects of the small molecules from CV (SMCV) and identify the active compounds that are responsible for the biological effects against glioblastoma multiforme cells. MATERIALS AND METHODS: The effects of SMCV/active compound on cytokine and MMP mRNA expressions and productions were assessed by quantitative reverse transcription polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA), respectively. An active compound from SMCV was identified with a bioassay-guided fractionation scheme. The potential mode of action of the active compound was further investigated by identifying the cell signaling pathway. The protein expressions of phospho-ERK, phospho-JNK and phospho-p38 MAPKs were measured by Western Blotting. The anti-invasive effect of SMCV/bioactive compound against T98G, lung carcinoma (A549), and breast adenocarcinoma (MDA-MB-231) cells were determined using invasion assay. RESULTS: Our results showed that SMCV had strong immunomodulatory effect by suppressing LPS-induced TNF-α production, whereas increasing poly I:C-induced IFN-ß level in PBMac. SMCV not only possessed indirect anti-cancer effect by suppressing TNF-α-induced MMP-3 production in glioblastoma T98G cells, but also directly reduced the invasion ability of malignant cells including T98G, A549 and MDA-MB-231. Using bioassay-guided fractionation scheme, we isolated 9-KODE methyl ester (compound AM) that was responsible for the bioactivity of SMCV. This compound suppressed TNF-α-induced MMP-3 production in T98G cells and the suppression may be correlated with the inactivation of p38 mitogen-activated protein kinase (MAPK) pathway. Moreover, compound AM also directly reduced T98G cell invasion. CONCLUSION: Results of our present study provides scientific evidence that SMCV possesses immunomodulatory and anti-cancer effects. Its bioactive compound, compound AM, is a potential new drug candidate against the invasion and metastasis of glioblastoma cells.


Assuntos
Glioblastoma , Proteínas Quinases Ativadas por Mitógeno , Humanos , Glioblastoma/tratamento farmacológico , Fatores Imunológicos/farmacologia , Metaloproteinase 3 da Matriz , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno , Fator de Necrose Tumoral alfa/metabolismo , Sistema de Sinalização das MAP Quinases , Metástase Neoplásica
3.
J Theor Biol ; 557: 111342, 2023 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-36368560

RESUMO

Glioblastoma multiforme (GBM) is one of the most deadly forms of cancer. Methods of characterizing these tumours are valuable for improving predictions of their progression and response to treatment. A mathematical model called the proliferation-invasion (PI) model has been used extensively in the literature to model the growth of these tumours, though it relies on known values of two key parameters: the tumour cell diffusivity and proliferation rate. Unfortunately, these parameters are difficult to estimate in a patient-specific manner, making personalized tumour forecasting challenging. In this paper, we develop and apply a deep learning model capable of making accurate estimates of these key GBM-characterizing parameters while simultaneously producing a full prediction of the tumour progression curve. Our method uses two sets of multi sequence MRI in order to produce estimations and relies on a preprocessing pipeline which includes brain tumour segmentation and conversion to tumour cellularity. We first apply our deep learning model to synthetic tumours to showcase the model's capabilities and identify situations where prediction errors are likely to occur. We then apply our model to a clinical dataset consisting of five patients diagnosed with GBM. For all patients, we derive evidence-based estimates for each of the PI model parameters and predictions for the future progression of the tumour, along with estimates of the parameter uncertainties. Our work provides a new, easily generalizable method for the estimation of patient-specific tumour parameters, which can be built upon to aid physicians in designing personalized treatments.


Assuntos
Neoplasias Encefálicas , Aprendizado Profundo , Glioblastoma , Humanos , Neoplasias Encefálicas/diagnóstico por imagem , Glioblastoma/diagnóstico por imagem , Incerteza , Contagem de Células
4.
Biochim Biophys Acta Mol Basis Dis ; 1869(1): 166571, 2023 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-36244542

RESUMO

Sustained proliferative signaling is a crucial hallmark and therapeutic target in glioblastoma (GBM); however, new intrinsic regulators and their underlying mechanisms remain to be elucidated. In this study, I kappa B kinase interacting protein (IKBIP) was identified to be correlated with the progression of GBM by analysis of The Cancer Genome Atlas (TCGA) data. TCGA database analysis indicated that higher IKBIP expression was associated with high tumor grade and poor prognosis in GBM patients, and these correlations were subsequently validated in clinical samples. IKBIP knockdown induced G1/S arrest by blocking the Cyclin D1/CDK4/CDK6/CDK2 pathway. Our results showed that IKBIP may bind directly to CDK4, a key cell cycle checkpoint protein, and prevent its ubiquitination-mediated degradation in GBM cells. An in vivo study confirmed that IKBIP knockdown strongly suppressed cell proliferation and tumor growth and prolonged survival in a mouse xenograft model established with human GBM cells. In conclusion, IKBIP functions as a novel driver of GBM by binding and stabilizing the CDK4 protein. IKBIP could be a potential therapeutic target in GBM.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Animais , Camundongos , Glioblastoma/metabolismo , Neoplasias Encefálicas/metabolismo , Proliferação de Células , Ubiquitinação , Biomarcadores/metabolismo , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo
5.
Int J Cancer ; 152(2): 308-319, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36054558

RESUMO

Detection of tumor progression in patients with glioblastoma remains a major challenge. Extracellular vesicles (EVs) are potential biomarkers and can be detected in the blood of patients with glioblastoma. In our study, we evaluated the potential of serum-derived EVs from glioblastoma patients to serve as biomarker for tumor progression. EVs from serum of glioblastoma patients and healthy volunteers were separated by size exclusion chromatography and ultracentrifugation. EV markers were defined by using a proximity-extension assay and bead-based flow cytometry. Tumor progression was defined according to modified RANO criteria. EVs from the serum of glioblastoma patients (n = 67) showed an upregulation of CD29, CD44, CD81, CD146, C1QA and histone H3 as compared to serum EVs from healthy volunteers (P value range: <.0001 to .08). For two independent cohorts of glioblastoma patients, we noted upregulation of C1QA, CD44 and histone H3 upon tumor progression, but not in patients with stable disease. In a multivariable logistic regression analysis, a combination of CD29, CD44, CD81, C1QA and histone H3 correlated with RANO-defined tumor progression with an AUC of 0.76. Measurement of CD29, CD44, CD81, C1QA and histone H3 in serum-derived EVs of glioblastoma patients, along with standard MRI assessment, has the potential to improve detection of true tumor progression and thus could be a useful biomarker for clinical decision making.


Assuntos
Vesículas Extracelulares , Glioblastoma , Humanos , Histonas , Proteínas Sanguíneas , Integrina beta1
6.
Semin Cell Dev Biol ; 133: 32-41, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-35697594

RESUMO

Extracellular vesicles (EVs) are membrane-delimited vesicular bodies carrying different molecules, classified according to their size, density, cargo, and origin. Research on this topic has been actively growing through the years, as EVs are associated with critical pathological processes such as neurodegenerative diseases and cancer. Despite that, studies exploring the physiological functions of EVs are sparse, with particular emphasis on their role in organismal development, initial cell differentiation, and morphogenesis. In this review, we explore the topic of EVs from a developmental perspective, discussing their role in the earliest cell-fate decisions and neural tissue morphogenesis. We focus on the function of EVs through development to highlight possible conserved or novel processes that can impact disease progression. Specifically, we take advantage of what was learned about their role in development so far to discuss EVs impact on glioblastoma, a particular brain tumor of stem-cell origin and poor prognosis, and how their function can be hijacked to improve current therapies.


Assuntos
Vesículas Extracelulares , Glioblastoma , Humanos , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Vesículas Extracelulares/patologia , Comunicação Celular , Células-Tronco , Diferenciação Celular
7.
Mol Med Rep ; 27(1)2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36367159

RESUMO

Glioblastoma is one of the most frequent primary brain tumors with a poor prognosis. Nevertheless, some patients show a prolonged survival. The aim of the present study was to compare the expression profiles of tumor derived microRNA (miR) of long­term survivors with those of short­term survivors in order to identify differentially expressed miRs as well as their target genes, which may elucidate mechanisms that play a role in varying tumor progression and, therefore, may influence survival. Formalin­fixed paraffin­embedded samples of 23 patients with glioblastoma were classified according to overall survival. Profiles of miR expression were determined using Nanostring technology. Expression levels of potential target genes of differentially expressed miRs were assessed using immunohistochemistry. MiR profiles of long­term survivors differed from those of short­term survivors. A total of three prominent differentially expressed miRs were highlighted: MiR­130b­3p, which is downregulated in long­term survivors, and miR­146b­5p and miR­148a­3p, which are upregulated in long­term survivors. Known tumor suppressor genes are among targets potentially affected by miR­130b­3p, whereas targets of miR­146b­5p and miR­148a­3p consist of several genes known to have a role in tumor invasion and aggressiveness. In conclusion, it was revealed that a type of miR­signature was associated with short­ and long­term survival, potentially serving as biomarker for disease progression and providing a base for further functional studies.


Assuntos
Neoplasias Encefálicas , Glioblastoma , MicroRNAs , Humanos , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Glioblastoma/patologia , MicroRNAs/genética , MicroRNAs/metabolismo
8.
Methods Mol Biol ; 2572: 117-127, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36161412

RESUMO

Glioblastoma (GBM) is the most common and dismal primary brain tumor. Unfortunately, despite multidisciplinary treatment, most patients will perish approximately 15 months after diagnosis. For this reason, there is an urgent need to improve our understanding of GBM tumor biology and develop novel therapies that can achieve better clinical outcomes. In this setting, three-dimensional tumor models have risen as more appropriate preclinical tools when compared to traditional cell cultures, given that two-dimensional (2D) cultures have failed to accurately recapitulate tumor biology and translate preclinical findings into patient benefits. Three-dimensional cultures using neurospheres, organoids, and organotypic better resemble original tumor genetic and epigenetic profiles, maintaining tumor microenvironment characteristics and mimicking cell-cell and cell-matrix interactions. This chapter summarizes our methods to generate well-characterized glioblastoma neurospheres, organoids, and organotypics.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Neoplasias Experimentais , Animais , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Glioblastoma/patologia , Humanos , Neoplasias Experimentais/patologia , Células-Tronco Neoplásicas/patologia , Organoides/patologia , Microambiente Tumoral
9.
Methods Mol Biol ; 2572: 101-116, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36161411

RESUMO

Vascular co-option is a non-angiogenic mechanism whereby tumor growth and progression move on by hijacking the pre-existing and nonmalignant blood vessels and is employed by various tumors to grow and metastasize.The histopathological identification of co-opted blood vessels is complex, and no specific markers were defined, but it is critical to develop new and possibly more effective therapeutic strategies. Here, in glioblastoma, we show that the co-opted blood vessels can be identified, by double immunohistochemical staining, as weak CD31+ vessels with reduced P-gp expression and proliferation and surrounded by highly proliferating and P-gp- or S100A10-expressing tumor cells. Results can be quantified by the Aperio Colocalization algorithm, which is a valid and robust method to handle and investigate large data sets.


Assuntos
Glioblastoma , Neovascularização Patológica , Formaldeído , Humanos , Neovascularização Patológica/patologia , Inclusão em Parafina , Coloração e Rotulagem
10.
Gene ; 848: 146895, 2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36122609

RESUMO

Glioblastoma (GBM) is the most common malignant brain tumor among adults. Cancer stem cells (CSCs) are known to drive treatment resistance and recurrence. However, a few CSC markers have been identified as therapeutic targets for GBM. This study aimed to show highly coexpressed genes in GBM CSCs and TCGA GBM samples and to identify possible therapeutic targets for GBM. The gene expression profiles of GBM CSCs were obtained from Gene Expression Omnibus database. After the differentially upregulated genes were screened, functional enrichment analyses were performed using DAVID and Reactome databases. For upregulated genes, biological processes were mainly associated with the regulation of transcription. Subsequently, a protein-protein interaction network was constructed for upregulated genes through STRING, in which DUSP6, FGFR3, EGFR, SOX2, NES, and PLP1 were further identified as hub genes via MCC and MNC methods. Expression profiles of hub genes and their association with survival were examined in TCGA GBM dataset using GEPIA2 platform. The expression levels of four hub genes were found to be increased in TCGA GBM samples. Of these, DUSP6 and SOX2 had prognostic value for patients with GBM. Molecular compounds targeting DUSP6 were searched through PubChem database. (E/Z)-BCI and BCI were found to be inhibitors of DUSP6. The molecular docking was performed using Autodock vina 1.02. The compounds showed strong binding capacities by forming various interactions with the ERK2 binding domain of DUSP6. Hence, the current study unravels the potential of (E/Z)-BCI and BCI compounds as possible anti-cancer molecules for GBM treatment.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Adulto , Neoplasias Encefálicas/patologia , Biologia Computacional/métodos , Receptores ErbB/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Glioblastoma/metabolismo , Humanos , Simulação de Acoplamento Molecular , Células-Tronco Neoplásicas/metabolismo
11.
BMC Med Genomics ; 15(1): 233, 2022 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-36333718

RESUMO

BACKGROUND: Glioblastoma (GBM), the most common glial primary brain tumour, is without exception lethal. Every year approximately 600 patients are diagnosed with this heterogeneous disease in The Netherlands. Despite neurosurgery, chemo -and radiation therapy, these tumours inevitably recur. Currently, there is no gold standard at time of recurrence and treatment options are limited. Unfortunately, the results of dedicated trials with new drugs have been very disappointing. The goal of the project is to obtain the evidence for changing standard of care (SOC) procedures to include whole genome sequencing (WGS) and consequently adapt care guidelines for this specific patient group with very poor prognosis by offering optimal and timely benefit from novel therapies, even in the absence of traditional registration trials for this small volume cancer indication. METHODS: The GLOW study is a prospective diagnostic cohort study executed through collaboration of the Hartwig Medical Foundation (Hartwig, a non-profit organisation) and twelve Dutch centers that perform neurosurgery and/or treat GBM patients. A total of 200 patients with a first recurrence of a glioblastoma will be included. Dual primary endpoint is the percentage of patients who receive targeted therapy based on the WGS report and overall survival. Secondary endpoints include WGS report success rate and number of targeted treatments available based on WGS reports and number of patients starting a treatment in presence of an actionable variant. At recurrence, study participants will undergo SOC neurosurgical resection. Tumour material will then, together with a blood sample, be sent to Hartwig where it will be analysed by WGS. A diagnostic report with therapy guidance, including potential matching off-label drugs and available clinical trials will then be sent back to the treating physician for discussing of the results in molecular tumour boards and targeted treatment decision making. DISCUSSION: The GLOW study aims to provide the scientific evidence for changing the SOC diagnostics for patients with a recurrent glioblastoma by investigating complete genome diagnostics to maximize treatment options for this patient group. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05186064.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Doença Crônica , Glioblastoma/diagnóstico , Glioblastoma/genética , Glioblastoma/terapia , Estudos Multicêntricos como Assunto , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/terapia , Estudos Prospectivos , Sequenciamento Completo do Genoma
12.
Int J Pharm ; 628: 122341, 2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36341916

RESUMO

Glioblastoma (GBM) recurrences are inevitable, and mainly originate from residual tumor cells and the presence of glioma stem cells (GSC) around the resection cavity borders. We previously showed that the local treatment of GBM with nanomedicine-based Lauroyl-gemcitabine lipid nanocapsules (GemC12-LNC) hydrogel delayed tumor onset in various preclinical models and can be used as a scaffold to deliver multiple drugs. However, it does not inhibit tumor relapse in the long-term. In this work, we aim at encapsulating an anti-GSC molecule in the GemC12-LNC hydrogel to eliminate both GBM cells and GSC. We performed a screening on GBM cell lines (GL261 and U-87 MG) and patient-derived GSC (GBM9) to select the anti-GSC molecule that could act synergically with GemC12. Based on our results, salinomycin (Sal) and curcumin (Cur) were selected for further development. Both GemC12-Sal-LNC and GemC12-Cur LNC showed similar size (55 nm), zeta potential (- 2 mV) and viscoelastic properties compared to the GemC12-LNC hydrogel. Encapsulation efficiency was above 95 %. Moreover, the GemC12-Sal-LNC hydrogel was stable for at least 6 months and released both drugs over 30 days in vitro. Both hydrogels inhibited the growth of GL261 and U-87 MG spheroids. Flow cytometry analysis showed that Sal reduced the GSC population in GL261 and U-87 MG cells. Our results show that the co-encapsulation of Sal in the GemC12-LNC hydrogel can reduce both GBM cells and GSC, and therefore might be promising to avoid the onset of GBM recurrences.


Assuntos
Neoplasias Encefálicas , Curcumina , Glioblastoma , Glioma , Humanos , Glioblastoma/metabolismo , Nanomedicina/métodos , Hidrogéis/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Lipídeos , Glioma/tratamento farmacológico , Curcumina/farmacologia , Células-Tronco Neoplásicas/metabolismo
13.
Cancer Biol Med ; 19(10)2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36350001

RESUMO

OBJECTIVE: IDH-mutant lower-grade gliomas (LGGs, grade 2 or 3) eventually transform into secondary grade 4 astrocytomas (sAIDHmut/G4). Here, we sought to describe the transformation time, risk factors, and outcomes in malignant transformation of IDH-mutant LGGs. METHODS: We screened data for 108 patients with sAIDHmut/G4 in the Chinese Glioma Genome Atlas who had initial IDH-mutant LGGs and underwent reoperation during 2005-2021. We evaluated the transformation time from IDH-mutant LGGs to sAIDHmut/G4, and associated risk factors and outcomes. Malignant transformation was defined as pathological confirmation of grade 4 astrocytoma. RESULTS: The median age of the 108 patients with IDH-mutant LGGs was 35 years (range, 19-54); the median age at transformation was 40 years (range, 25-62); and the median follow-up time for all patients was 146 months (range, 121-171). The average transformation time was 58.8 months for all patients with LGGs (range, 5.9-208.1); 63.5 and 51.9 months for grade 2 and 3 gliomas, respectively; and 58.4 and 78.1 months for IDH-mutant/1p/19q-non-codeleted astrocytomas and IDH-mutant/1p/19q-codeleted oligodendrogliomas, respectively. Univariate and multivariate analysis indicated that radiotherapy [hazard ratio (HR), 0.29; 95% confidence interval (CI), 0.137-0.595; P = 0.001] and non-A blood type (HR, 0.37; 95% CI, 0.203-0.680; P = 0.001) were protective factors against delayed malignant transformation. Radiotherapy was associated with improved survival after transformation (HR, 0.44; 95% CI, 0.241-0.803; P = 0.008), overall survival (HR, 0.50; 95% CI, 0.265-0.972; P = 0.041), and progression-free survival (HR, 0.25; 95% CI, 0.133-0.479; P < 0.0001) in patients with IDH-mutant gliomas. CONCLUSIONS: Radiotherapy is associated with delayed malignant transformation and improved survival in patients with IDH-mutant gliomas.


Assuntos
Astrocitoma , Neoplasias Encefálicas , Glioblastoma , Glioma , Oligodendroglioma , Humanos , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Isocitrato Desidrogenase/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/patologia , Glioma/genética , Glioma/radioterapia , Glioma/patologia , Astrocitoma/genética , Astrocitoma/radioterapia , Astrocitoma/cirurgia , Transformação Celular Neoplásica/genética
14.
Cancer Biol Med ; 19(10)2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36350002

RESUMO

Understanding the racial specificities of diseases-such as adult diffuse glioma, the most common primary malignant tumor of the central nervous system-is a critical step toward precision medicine. Here, we comprehensively review studies of gliomas in East Asian populations and other ancestry groups to clarify the racial differences in terms of epidemiology and genomic characteristics. Overall, we observed a lower glioma incidence in East Asians than in Whites; notably, patients with glioblastoma had significantly younger ages of onset and longer overall survival than the Whites. Multiple genome-wide association studies of various cohorts have revealed single nucleotide polymorphisms associated with overall and subtype-specific glioma susceptibility. Notably, only 3 risk loci-5p15.33, 11q23.3, and 20q13.33-were shared between patients with East Asian and White ancestry, whereas other loci predominated only in particular populations. For instance, risk loci 12p11.23, 15q15-21.1, and 19p13.12 were reported in East Asians, whereas risk loci 8q24.21, 1p31.3, and 1q32.1 were reported in studies in White patients. Although the somatic mutational profiles of gliomas between East Asians and non-East Asians were broadly consistent, a lower incidence of EGFR amplification in glioblastoma and a higher incidence of 1p19q-IDH-TERT triple-negative low-grade glioma were observed in East Asian cohorts. By summarizing large-scale disease surveillance, germline, and somatic genomic studies, this review reveals the unique characteristics of adult diffuse glioma among East Asians, to guide clinical management and policy design focused on patients with East Asian ancestry.


Assuntos
Glioblastoma , Glioma , Adulto , Humanos , Glioblastoma/genética , Estudo de Associação Genômica Ampla , Glioma/epidemiologia , Glioma/genética , Asiáticos/genética , Mutação
15.
Cancer Biol Med ; 19(10)2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36350010

RESUMO

OBJECTIVE: We aimed to summarize the clinicopathological characteristics and prognostic features of various molecular subtypes of diffuse gliomas (DGs) in the Chinese population. METHODS: In total, 1,418 patients diagnosed with DG between 2011 and 2017 were classified into 5 molecular subtypes according to the 2016 WHO classification of central nervous system tumors. The IDH mutation status was determined by immunohistochemistry and/or DNA sequencing, and 1p/19q codeletion was detected with fluorescence in situ hybridization. The median clinical follow-up time was 1,076 days. T-tests and chi-square tests were used to compare clinicopathological characteristics. Kaplan-Meier and Cox regression methods were used to evaluate prognostic factors. RESULTS: Our cohort included 15.5% lower-grade gliomas, IDH-mutant and 1p/19q-codeleted (LGG-IDHm-1p/19q); 18.1% lower-grade gliomas, IDH-mutant (LGG-IDHm); 13.1% lower-grade gliomas, IDH-wildtype (LGG-IDHwt); 36.1% glioblastoma, IDH-wildtype (GBM-IDHwt); and 17.2% glioblastoma, IDH-mutant (GBM-IDHm). Approximately 63.3% of the enrolled primary gliomas, and the median overall survival times for LGG-IDHm, LGG-IDHwt, GBM-IDHwt, and GBM-IDHm subtypes were 75.97, 34.47, 11.57, and 15.17 months, respectively. The 5-year survival rate of LGG-IDHm-1p/19q was 76.54%. We observed a significant association between high resection rate and favorable survival outcomes across all subtypes of primary tumors. We also observed a significant role of chemotherapy in prolonging overall survival for GBM-IDHwt and GBM-IDHm, and in prolonging post-relapse survival for the 2 recurrent GBM subtypes. CONCLUSIONS: By controlling for molecular subtypes, we found that resection rate and chemotherapy were 2 prognostic factors associated with survival outcomes in a Chinese cohort with DG.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Isocitrato Desidrogenase/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Estudos Retrospectivos , Hibridização in Situ Fluorescente , Mutação , Recidiva Local de Neoplasia , Glioma/genética , Glioma/terapia
16.
Neurol India ; 70(5): 2086-2092, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36352613

RESUMO

Objectives: Different variant of GBM has been reported viz. Epithelioid Glioblastoma (GBM-E), Rhabdoid GBM (GBM-R), Small cell GBM (GBM-SC), Giant cell GBM (GBM-GC), GBM with neuro ectodermal differentiation (GBM-PNET) with unknown behavior. Materials: We conducted a systematic review and individual patient data analysis of these rare GBM variants. We searched PubMed, google search, and Cochrane library for eligible studies till July 1st 2016 published in English language and collected data regarding age, sex, subtype and treatment received, Progression Free Survival (PFS), Overall Survival (OS). Statistical Package for social sciences (SPSS) v16 software was used for all statistical analysis. Results: We retrieved data of 196 patients with rare GBM subtypes. Among these GBM-GC is commonest (51%), followed by GBM-R (19%), GBM-PNET (13%), GBM-SC (9%) and GBM-E (8%). Median age at diagnosis was 38, 40, 43.5, 69.5 and 18 years, respectively. Male: female ratio was 2:1 for GBM-E, and 1:3 for GBM-SC. Maximal safe resection followed by adjuvant local radiation was used for most of the patients. However, 6 patients with GBM-PNET, 3 each of GBM-E, GBM-SC received adjuvant craniospinal radiation. Out of 88 patients who received chemotherapy, 64 received Temozolomide alone or combination chemotherapy containing Temozolomide. Median PFS and OS for the entire cohort were 9 and 16 months. In univariate analysis, patient with a Gross Total Resection had significantly better PFS and OS compared to those with a Sub Total Resection [23 vs. 13 months (p-0.01)]. Median OS for GBM PNET, GBM-GC, GBM-SC, GBM-R and GBM-E were 32, 18.3, 11, 12 and 7.7 months, respectively (P = 0.001). Interestingly, 31.3%, 37.8% of patients with GBM-E, GBM-R had CSF dissemination. Conclusion: Overall cohort of rarer GBM variant has equivalent survival compared to GBM not otherwise specified. However, epithelioid and Rhabdoid GBM has worst survival and one third shows CSF dissemination.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Tumores Neuroectodérmicos Primitivos , Humanos , Masculino , Feminino , Temozolomida/uso terapêutico , Análise de Dados , Neoplasias Encefálicas/cirurgia , Estudos Retrospectivos , Tumores Neuroectodérmicos Primitivos/tratamento farmacológico , Antineoplásicos Alquilantes/uso terapêutico
17.
Acta Med Okayama ; 76(5): 489-502, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36352795

RESUMO

Glioblastoma (GBM) is a fatal primary malignant brain tumor in adults. Despite decades of research, the prognosis for GBM patients is still disappointing. One major reason for the intense therapeutic resistance of GBM is inter- and intra-tumor heterogeneity. GBM-intrinsic transcriptional profiling has suggested the presence of at least three subtypes of GBM: the proneural, classic, and mesenchymal subtypes. The mesenchymal subtype is the most aggressive, and patients with the mesenchymal subtype of primary and recurrent tumors tend to have a worse prognosis compared with patients with the other subtypes. Furthermore, GBM can shift from other subtypes to the mesenchymal subtype over the course of disease progression or recurrence. This phenotypic transition is driven by diverse tumor-intrinsic molecular mechanisms or microenvironmental factors. Thus, better understanding of the plastic nature of mesenchymal transition in GBM is pivotal to developing new therapeutic strategies. In this review, we provide a comprehensive overview of the current understanding of the elements involved in the mesenchymal transition of GBM and discuss future perspectives.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Adulto , Humanos , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/terapia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Prognóstico , Regulação Neoplásica da Expressão Gênica
18.
Molecules ; 27(21)2022 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-36364024

RESUMO

Glioblastoma multiforme (GBM) is a tumor of glial origin and is the most malignant, aggressive and prevalent type, with the highest mortality rate in adult brain cancer. Surgical resection of the tumor followed by Temozolomide (TMZ) therapy is currently available, but the development of resistance to TMZ is a common limiting factor in effective treatment. The present study investigated the potential interactions of TMZ with several secretory proteins involved in various molecular and cellular processes in GBM. Automated docking studies were performed using AutoDock 4.2, which showed an encouraging binding affinity of TMZ towards all targeted proteins, with the strongest interaction and binding affinity with GDF1 and SLIT1, followed by NPTX1, CREG2 and SERPINI, among the selected proteins. Molecular dynamics (MD) simulations of protein-ligand complexes were performed via CABS-flex V2.0 and the iMOD server to evaluate the root-mean-square fluctuations (RMSFs) and measure protein stability, respectively. The results showed that docked models were more flexible and stable with TMZ, suggesting that it may be able to target putative proteins implicated in gliomagenesis that may impact radioresistance. However, additional in vitro and in vivo investigations can ascertain the potential of the selected proteins to serve as novel targets for TMZ for GBM treatment.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Temozolomida/farmacologia , Glioblastoma/metabolismo , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Neoplasias Encefálicas/patologia , Proteínas Repressoras/metabolismo
19.
Nat Commun ; 13(1): 6835, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36369424

RESUMO

Glioblastoma multiforme (GBM) is one of the most fatal malignancies due to the existence of blood-brain barrier (BBB) and the difficulty to maintain an effective drug accumulation in deep GBM lesions. Here we present a biomimetic nanogel system that can be precisely activated by near infrared (NIR) irradiation to achieve BBB crossing and deep tumor penetration of drugs. Synthesized by crosslinking pullulan and poly(deca-4,6-diynedioic acid) (PDDA) and loaded with temozolomide and indocyanine green (ICG), the nanogels are inert to endogenous oxidative conditions but can be selectively disintegrated by ICG-generated reactive oxygen species upon NIR irradiation. Camouflaging the nanogels with apolipoprotein E peptide-decorated erythrocyte membrane further allows prolonged blood circulation and active tumor targeting. The precisely controlled NIR irradiation on tumor lesions excites ICG and deforms the cumulated nanogels to trigger burst drug release for facilitated BBB permeation and infiltration into distal tumor cells. These NIR-activatable biomimetic nanogels suppress the tumor growth in orthotopic GBM and GBM stem cells-bearing mouse models with significantly extended survival.


Assuntos
Glioblastoma , Camundongos , Animais , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Nanogéis , Biomimética , Temozolomida , Verde de Indocianina , Linhagem Celular Tumoral
20.
Neurosurg Rev ; 45(6): 3619-3628, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36350492

RESUMO

Glioblastoma is the most common primary malignant brain tumor in the adult population. It causes the patient to incur a great deal of malady. Even with the advances in management and the Stupp protocol in place, the prognosis remains grim. There are various parameters to evaluate patients' performance status and frailty pre-operatively, but these are mostly subjective and thus suffer from inter-observer variability. Assessment of sarcopenia serves as an objective parameter to assess the patient's performance status pre-operatively. Temporalis muscle thickness serves as a surrogate to assess sarcopenia in patients with glioblastoma. We conducted a literature review and meta-analysis to determine the prognostic implications of temporalis muscle thickness in 3283 patients with primary glioblastoma. The pooled overall survival hazard's ratio of thick versus thin TMT was 0.54. The pooled progression-free survival hazard's ratio of thick versus thin TMT was 0.38. Thus, the main finding of this study is that thicker temporal muscle is associated with better OS and PFS as compared to thinner temporal muscle. We thus conclude that TMT is a viable surrogate for predicting sarcopenia and survival in primary glioblastoma. TMT measurement is extremely easy and can be incorporated as a part of the routine neurosurgical workflow in these patients. Survival prediction will help inform treatment decisions in glioblastoma patients having poor prognosis, at the initial diagnosis itself.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Sarcopenia , Adulto , Humanos , Prognóstico , Músculo Temporal/patologia , Neoplasias Encefálicas/patologia , Sarcopenia/diagnóstico , Sarcopenia/patologia
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