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1.
Diagn Interv Radiol ; 27(6): 716-724, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34792025

RESUMO

PURPOSE: We aimed to assess the diagnostic performance of radiomics using machine learning algorithms to predict the methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) promoter in glioma patients. METHODS: A comprehensive literature search of PubMed, EMBASE, and Web of Science until 27 July 2021 was performed to identify eligible studies. Stata SE 15.0 and Meta-Disc 1.4 were used for data analysis. RESULTS: A total of fifteen studies with 1663 patients were included: five studies with training and validation cohorts and ten with only training cohorts. The pooled sensitivity and specificity of machine learning for predicting MGMT promoter methylation in gliomas were 85% (95% CI 79%-90%) and 84% (95% CI 78%-88%) in the training cohort (n=15) and 84% (95% CI 70%-92%) and 78% (95% CI 63%-88%) in the validation cohort (n=5). The AUC was 0.91 (95% CI 0.88-0.93) in the training cohort and 0.88 (95% CI 0.85-0.91) in the validation cohort. The meta-regression demonstrated that magnetic resonance imaging sequences were related to heterogeneity. The sensitivity analysis showed that heterogeneity was reduced by excluding one study with the lowest diagnostic performance. CONCLUSION: This meta-analysis demonstrated that machine learning is a promising, reliable and repeatable candidate method for predicting MGMT promoter methylation status in glioma and showed a higher performance than non-machine learning methods.


Assuntos
Neoplasias Encefálicas , Glioma , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioma/diagnóstico por imagem , Glioma/genética , Humanos , Aprendizado de Máquina , Metilação , Proteínas Supressoras de Tumor/genética
2.
BMC Neurol ; 21(1): 460, 2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34814870

RESUMO

BACKGROUND: The aim of this study was to investigate the relationship between tumor biology and values of cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT), time to peak (TTP), permeability surface (PS) of tumor in patients with glioma. METHODS: Forty-six patients with glioma were involved in the study. Histopathologic and molecular pathology diagnoses were obtained by tumor resection, and all patients accepted perfusion computed tomography (PCT) before operation. Regions of interests were placed manually at tumor and contralateral normal-appearing thalamus. The parameters of tumor were divided by those of contralateral normal-appearing thalamus to normalize at tumor (relative [r] CBV, rCBF, rMTT, rTTP, rPS). The relationships of the parameters, world health organization (WHO) grade, molecular pathological findings were analysed. RESULTS: The rCBV, rMTT and rPS of patients are positively related to the pathological classification (P < 0.05). The values of rCBV and rPS in IDH mutated patients were lower than those IDH wild-type. The values of rCBF in patients with MGMT methylation were lower than those MGMT unmethylation (P < 0.05). The MVD of TERT wild-type group was lower than TERT mutated group (P < 0.05). The values of rCBV were significant difference in the four molecular groups divided by the combined IDH/TERT classification (P < 0.05). The progression free survival (PFS) and overall survival (OS) were significant difference in the four molecular groups divided by the combined IDH/TERT classification (P < 0.05). CONCLUSIONS: Our study introduces and supports the changes of glioma flow perfusion may be closely related to its biological characteristics.


Assuntos
Neoplasias Encefálicas , Glioma , Telomerase , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Circulação Cerebrovascular , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioma/diagnóstico por imagem , Glioma/genética , Humanos , Perfusão , Imagem de Perfusão , Tomografia Computadorizada por Raios X , Proteínas Supressoras de Tumor/genética
3.
World J Gastroenterol ; 27(34): 5737-5752, 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34629798

RESUMO

BACKGROUND: Identifying novel colorectal cancer (CRC) prognostic biomarkers is crucial to helping clinicians make appropriate therapy decisions. Melatonin plays a major role in managing the circadian rhythm and exerts oncostatic effects on different kinds of tumours. AIM: To explore the relationship between MTNR1B single-nucleotide polymorphism (SNPs) combined with gene hypermethylation and CRC prognosis. METHODS: A total of 94 CRC tumour tissues were investigated. Genotyping for the four MTNR1B SNPs (rs1387153, rs2166706, rs10830963, and rs1447352) was performed using multiplex polymerase chain reaction. The relationships between the MTNR1B SNPs and CRC 5-year overall survival (OS) was assessed by calculating hazard ratios with 95%CIs. RESULTS: All SNPs (rs1387153, rs2166706, rs10830963, and rs1447352) were correlated with decreased 5-year OS. In stratified analysis, rs1387153, rs10830963, and rs1447352 risk genotype combined with CDKN2A and MGMT methylation status were associated with 5-year OS. A strong cumulative effect of the four polymorphisms on CRC prognosis was observed. Four haplotypes of MTNR1B SNPs were also associated with the 5-year OS. MTNR1B SNPs combined with CDKN2A and MGMT gene methylation status could be used to predict shorter CRC survival. CONCLUSION: The novel genetic biomarkers combined with epigenetic biomarkers may be predictive tool for CRC prognosis and thus could be used to individualise treatment for patients with CRC.


Assuntos
Neoplasias Colorretais , Metilação de DNA , Neoplasias Colorretais/genética , Inibidor p16 de Quinase Dependente de Ciclina , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Humanos , Polimorfismo de Nucleotídeo Único , Prognóstico , Receptor MT2 de Melatonina/genética , Taiwan/epidemiologia , Proteínas Supressoras de Tumor/genética
4.
Free Radic Biol Med ; 176: 257-264, 2021 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-34624481

RESUMO

The MTH1 (NUDT1) gene, because it is frequently upregulated in many types of human cancers, has been considered a general marker of carcinogenesis for over two decades. The MTH1 protein hydrolyzes the oxidized mutagenic DNA precursor, 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGTP), to the corresponding 5'-monophosphate and inorganic pyrophosphate. This prevents its incorporation into DNA by DNA polymerases and protects cells from the accumulation of 8-oxo-dGTP-induced point mutations. Elevated MTH1 mRNA and protein in many types of human cancer indicate a worse prognosis. However, the enzymatic activity of MTH1 has remained largely uninvestigated in this context. Therefore, we have set out to determine the specific 8-oxo-dGTPase activity of MTH1 in 57 pairs of human colorectal cancers (CRC) and adjacent cancer-free tissues (CFCF). The goal was to ascertain the potential for measuring this enzymatic activity as a way to differentiate cancerous from non-cancerous specimens of the intestine, as well as defining its capabilities as a prognostic value for disease-free survival. We found that 79% of CRC tumors exhibited a higher MTH1 activity than did CFCF, with a significant 1.6-fold increase in overall median value (p < 1E-6). The 8-oxo-dGTPase in both tissues was proportional to the corresponding levels of MTH1 protein, as assayed by Western blotting. Activity higher than the ROC-optimized threshold (AUC = 0.71) indicated cancerous tissue, with a 54% sensitivity and an 83% specificity. Postoperative fate followed for up to 100 months showed that higher 8-oxo-dGTPase, in either the CFCF or the CRC tumor, clearly lowered the probability of a relapse-free survival, although borderline statistical significance (p < 0.05) was crossed only for the CFCF.


Assuntos
Neoplasias Colorretais , Recidiva Local de Neoplasia , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/genética , Enzimas Reparadoras do DNA/genética , Humanos , Monoéster Fosfórico Hidrolases/genética , Prognóstico
5.
Elife ; 102021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34477552

RESUMO

DNA double-strand break (DSB) repair by homologous recombination (HR) is thought to be restricted to the S- and G2- phases of the cell cycle in part due to 53BP1 antagonizing DNA end resection in G1-phase and non-cycling quiescent (G0) cells. Here, we show that LIN37, a component of the DREAM transcriptional repressor, functions in a 53BP1-independent manner to prevent DNA end resection and HR in G0 cells. Loss of LIN37 leads to the expression of HR proteins, including BRCA1, BRCA2, PALB2, and RAD51, and promotes DNA end resection in G0 cells even in the presence of 53BP1. In contrast to 53BP1-deficiency, DNA end resection in LIN37-deficient G0 cells depends on BRCA1 and leads to RAD51 filament formation and HR. LIN37 is not required to protect DNA ends in cycling cells at G1-phase. Thus, LIN37 regulates a novel 53BP1-independent cell phase-specific DNA end protection pathway that functions uniquely in quiescent cells.


Assuntos
Quebras de DNA de Cadeia Dupla , Reparo do DNA por Junção de Extremidades , Rad51 Recombinase/metabolismo , Transativadores/metabolismo , Proteína BRCA1/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Replicação do DNA , Fase G1 , Fase G2 , Recombinação Homóloga , Humanos , Fase S , Transativadores/genética , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo
6.
Neuro Oncol ; 23(9): 1457-1469, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34467991

RESUMO

BACKGROUND: The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) causes resistance of tumor cells to alkylating agents. It is a predictive biomarker in high-grade gliomas treated with temozolomide, however, there is no consensus on which test method, methylation sites, and cutoff values to use. METHODS: We performed a Cochrane Review to examine studies using different techniques to measure MGMT and predict survival in glioblastoma patients treated with temozolomide. Eligible longitudinal studies included (i) adults with glioblastoma treated with temozolomide with or without radiotherapy, or surgery; (ii) where MGMT status was determined in tumor tissue, and assessed by 1 or more technique; and (iii) where overall survival was an outcome parameter, with sufficient information to estimate hazard ratios (HRs). Two or more methods were compared in 32 independent cohorts with 3474 patients. RESULTS: Methylation-specific PCR (MSP) and pyrosequencing (PSQ) techniques were more prognostic than immunohistochemistry for MGMT protein, and PSQ is a slightly better predictor than MSP. CONCLUSIONS: We cannot draw strong conclusions about use of frozen tissue vs formalin-fixed paraffin-embedded in MSP and PSQ. Also, our meta-analysis does not provide strong evidence about the best CpG sites or threshold. MSP has been studied mainly for CpG sites 76-80 and 84-87 and PSQ at CpG sites ranging from 72 to 95. A cutoff threshold of 9% for CpG sites 74-78 performed better than higher thresholds of 28% or 29% in 2 of the 3 good-quality studies. About 190 studies were identified presenting HRs from survival analysis in patients in which MGMT methylation was measured by 1 technique only.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Humanos , Metilação , Regiões Promotoras Genéticas , Temozolomida/uso terapêutico , Proteínas Supressoras de Tumor/genética
7.
Int J Mol Sci ; 22(18)2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34576232

RESUMO

Neuroblastoma, the most common extra-cranial solid tumor of early childhood, is one of the major therapeutic challenges in child oncology: it is highly heterogenic at a genetic, biological, and clinical level. The high-risk cases have one of the least favorable outcomes amongst pediatric tumors, and the mortality rate is still high, regardless of the use of intensive multimodality therapies. Here, we observed that neuroblastoma cells display an increased expression of Cockayne Syndrome group B (CSB), a pleiotropic protein involved in multiple functions such as DNA repair, transcription, mitochondrial homeostasis, and cell division, and were recently found to confer cell robustness when they are up-regulated. In this study, we demonstrated that RNAi-mediated suppression of CSB drastically impairs tumorigenicity of neuroblastoma cells by hampering their proliferative, clonogenic, and invasive capabilities. In particular, we observed that CSB ablation induces cytokinesis failure, leading to caspases 9 and 3 activation and, subsequently, to massive apoptotic cell death. Worthy of note, a new frontier in cancer treatment, already proved to be successful, is cytokinesis-failure-induced cell death. In this context, CSB ablation seems to be a new and promising anticancer strategy for neuroblastoma therapy.


Assuntos
Citocinese/fisiologia , DNA Helicases/fisiologia , Enzimas Reparadoras do DNA/fisiologia , Neuroblastoma/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/fisiologia , Interferência de RNA , Apoptose , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Centrossomo , DNA Helicases/genética , DNA Helicases/metabolismo , Reparo do DNA , Enzimas Reparadoras do DNA/genética , Humanos , Proteínas de Ligação a Poli-ADP-Ribose/genética , Fuso Acromático
8.
Cancer Sci ; 112(11): 4736-4747, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34536314

RESUMO

Glioblastomas (GBM) often acquire resistance against temozolomide (TMZ) after continuous treatment and recur as TMZ-resistant GBM (TMZ-R-GBM). Lomustine (CCNU) and nimustine (ACNU), which were previously used as standard therapeutic agents against GBM before TMZ, have occasionally been used for the salvage therapy of TMZ-R-GBM; however, their efficacy has not yet been thoroughly examined. Therefore, we investigated the antitumor effects of CCNU and ACNU against TMZ-R-GBM. As a model of TMZ-R-GBM, TMZ resistant clones of human GBM cell lines (U87, U251MG, and U343MG) were established (TMZ-R-cells) by the culture of each GBM cells under continuous TMZ treatment, and the antitumor effects of TMZ, CCNU, or ACNU against these cells were analyzed in vitro and in vivo. As a result, although growth arrest and apoptosis were triggered in all TMZ-R-cells after the administration of each drug, the antitumor effects of TMZ against TMZ-R-cells were significantly reduced compared to those of parental cells, whereas CCNU and ACNU demonstrated efficient antitumor effects on TMZ-R-cells as well as parental cells. It was also demonstrated that TMZ resistance of TMZ-R-cells was regulated at the initiation of DNA damage response. Furthermore, survival in mice was significantly prolonged by systemic treatment with CCNU or ACNU but not TMZ after implantation of TMZ-R-cells. These findings suggest that CCNU or ACNU may serve as a therapeutic agent in salvage treatment against TMZ-R-GBM.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Glioblastoma/tratamento farmacológico , Lomustina/uso terapêutico , Nimustina/uso terapêutico , Temozolomida/uso terapêutico , Animais , Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/metabolismo , Metilases de Modificação do DNA/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Glioblastoma/metabolismo , Histonas/metabolismo , Humanos , Injeções Intraperitoneais , Lomustina/administração & dosagem , Metilação , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Recidiva Local de Neoplasia/tratamento farmacológico , Nimustina/administração & dosagem , Terapia de Salvação/métodos , Proteínas Supressoras de Tumor/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
9.
CNS Oncol ; 10(3): CNS74, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34486380

RESUMO

Aim: To define the optimal cutoff point for determining methylation status of O6-methylguanine-DNA methyltransferase (MGMT) by pyrosequencing in glioblastoma. Patients & methods: A retrospective study of 109 glioblastoma patients was performed to determine the optimal cutoff point for MGMT methylation status. Results: Receiver operating characteristic (ROC) analysis revealed 21% as the optimal cutoff (sensitivity: 68%; specificity: 59%) for MGMT methylation corresponding with the highest likelihood ratio of 1.66 and accuracy of 0.65. Methylation status (hazard ratio: 0.453; 95% CI: 0.279-0.735; p = 0.001) was associated with better overall survival. The crude model indicated linearity between methylation percent and survival rate; an increase of 10% of methylation resulted in a reduction of risk of death by 20% (p = 0.004). Conclusion: ROC analysis determined 21% as the optimal cutoff point for MGMT methylation status by pyrosequencing.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Metilação de DNA/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Humanos , Estudos Retrospectivos , Proteínas Supressoras de Tumor/genética
10.
Nature ; 598(7880): 368-372, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34526721

RESUMO

Transcription-coupled DNA repair removes bulky DNA lesions from the genome1,2 and protects cells against ultraviolet (UV) irradiation3. Transcription-coupled DNA repair begins when RNA polymerase II (Pol II) stalls at a DNA lesion and recruits the Cockayne syndrome protein CSB, the E3 ubiquitin ligase, CRL4CSA and UV-stimulated scaffold protein A (UVSSA)3. Here we provide five high-resolution structures of Pol II transcription complexes containing human transcription-coupled DNA repair factors and the elongation factors PAF1 complex (PAF) and SPT6. Together with biochemical and published3,4 data, the structures provide a model for transcription-repair coupling. Stalling of Pol II at a DNA lesion triggers replacement of the elongation factor DSIF by CSB, which binds to PAF and moves upstream DNA to SPT6. The resulting elongation complex, ECTCR, uses the CSA-stimulated translocase activity of CSB to pull on upstream DNA and push Pol II forward. If the lesion cannot be bypassed, CRL4CSA spans over the Pol II clamp and ubiquitylates the RPB1 residue K1268, enabling recruitment of TFIIH to UVSSA and DNA repair. Conformational changes in CRL4CSA lead to ubiquitylation of CSB and to release of transcription-coupled DNA repair factors before transcription may continue over repaired DNA.


Assuntos
Microscopia Crioeletrônica , Reparo do DNA , Complexos Multiproteicos/química , Complexos Multiproteicos/ultraestrutura , RNA Polimerase II/química , RNA Polimerase II/ultraestrutura , Transcrição Genética , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Proteínas de Transporte/ultraestrutura , DNA Helicases/química , DNA Helicases/metabolismo , DNA Helicases/ultraestrutura , Enzimas Reparadoras do DNA/química , Enzimas Reparadoras do DNA/metabolismo , Enzimas Reparadoras do DNA/ultraestrutura , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/ultraestrutura , Humanos , Modelos Moleculares , Complexos Multiproteicos/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/química , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/ultraestrutura , RNA Polimerase II/metabolismo , Elongação da Transcrição Genética , Fator de Transcrição TFIIH/química , Fator de Transcrição TFIIH/metabolismo , Fator de Transcrição TFIIH/ultraestrutura , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo , Fatores de Transcrição/ultraestrutura , Ubiquitina-Proteína Ligases/química , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/ultraestrutura , Ubiquitinação
11.
BMC Cancer ; 21(1): 1025, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34525976

RESUMO

BACKGROUND: Mutations in driver genes such as IDH and BRAF have been identified in gliomas. Meanwhile, dysregulations in the p53, RB1, and MAPK and/or PI3K pathways are involved in the molecular pathogenesis of glioblastoma. RAS family genes activate MAPK through activation of RAF and PI3K to promote cell proliferation. RAS mutations are a well-known driver of mutation in many types of cancers, but knowledge of their significance for glioma is insufficient. The purpose of this study was to reveal the frequency and the clinical phenotype of RAS mutant in gliomas. METHODS: This study analysed RAS mutations and their clinical significance in 242 gliomas that were stored as unfixed or cryopreserved specimens removed at Kyoto University and Osaka National Hospital between May 2006 and October 2017. The hot spots mutation of IDH1/2, H3F3A, HIST1H3B, and TERT promoter and exon 2 and exon 3 of KRAS, HRAS, and NRAS were analysed with Sanger sequencing method, and 1p/19q codeletion was analysed with multiplex ligation-dependent probe amplification. DNA methylation array was performed in some RAS mutant tumours to improve accuracy of diagnosis. RESULTS: RAS mutations were identified in four gliomas with three KRAS mutations and one NRAS mutation in one anaplastic oligodendroglioma, two anaplastic astrocytomas (IDH wild-type in each), and one ganglioglioma. RAS-mutant gliomas were identified with various types of glioma histology. CONCLUSION: RAS mutation appears infrequent, and it is not associated with any specific histological phenotype of glioma.


Assuntos
Neoplasias Encefálicas/genética , Genes ras/genética , Glioma/genética , Mutação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Astrocitoma/genética , Neoplasias Encefálicas/patologia , Criança , Pré-Escolar , Metilação de DNA , Metilases de Modificação do DNA/metabolismo , Análise Mutacional de DNA/métodos , Enzimas Reparadoras do DNA/metabolismo , Éxons/genética , Feminino , Glioblastoma/genética , Glioma/patologia , Histonas/genética , Humanos , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Oligodendroglioma/genética , Fenótipo , Regiões Promotoras Genéticas , Telomerase/genética , Proteínas Supressoras de Tumor/metabolismo , Adulto Jovem
12.
Magn Reson Imaging ; 83: 189-195, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34506909

RESUMO

PURPOSE: To investigate the feasibility for preoperative prediction of IDH mutation and MGMT promoter methylation status in glioblastomas(GBMs) by intravoxel incoherent motion(IVIM) and dynamic susceptibility contrast(DSC). METHODS: Preoperative IVIM and DSC images of 71 patients(IDH mutation:45, IDH wildtype: 26; MGMT methylation: 31, MGMT unmethylation:40) with glioblastomas were analyzed retrospectively. Perfusion parameters including microcirculation perfusion coefficient(D*), perfusion fraction(f), cerebral blood volume(CBV) and cerebral blood flow(CBF) were measured. Corrected perfusion parameters containing corrected perfusion coefficient(ADCperf) and simplified perfusion fraction(SPF) were from the simplified IVIM with 3 b values. Correlations among parameters were analyzed by Spearman correlation. All parameters were compared with Mann-Whitney U test. Univariate and multivariate logistic regression models were constructed. The receiver operating characteristic(ROC) curve was analyzed. RESULTS: The IVIM parameters showed merely moderate correlations with CBV and showed no correlation with CBF. IDH mutation GBMs showed lower D*, ADCperf, SPF, CBV and higher f than IDH wildtype GBMs(all p < 0.05). D* was the independent predictor for IDH mutation with the highest AUC of 0.912(95%CI: 0.821-0.966). The D*, ADCperf, SPF and CBV of MGMT promoter methylation GBMs were lower than unmethylation GBMs while f was higher(all p < 0.05). Multivariate model showed the highest prediction efficacy for MGMT promoter methylation with an AUC of 0.915(95%CI: 0.824-0.968). The CBF was not useful in distinguishing IDH mutation and MGMT promoter methylation status(p = 0.055, 0.215). CONCLUSION: IDH mutation and MGMT promoter methylation status in GBMs can be assessed effectively by IVIM and DSC. Besides, D* was the independent predictor of IDH mutation status.


Assuntos
Neoplasias Encefálicas , Metilases de Modificação do DNA , Enzimas Reparadoras do DNA , Glioblastoma , Isocitrato Desidrogenase/genética , Proteínas Supressoras de Tumor , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Imagem de Difusão por Ressonância Magnética , Glioblastoma/diagnóstico por imagem , Glioblastoma/genética , Humanos , Imageamento por Ressonância Magnética , Metilação , Mutação , Perfusão , Estudos Retrospectivos , Proteínas Supressoras de Tumor/genética
13.
Mol Cell ; 81(16): 3400-3409.e3, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34352203

RESUMO

Non-homologous end joining (NHEJ) is one of two critical mechanisms utilized in humans to repair DNA double-strand breaks (DSBs). Unrepaired or incorrect repair of DSBs can lead to apoptosis or cancer. NHEJ involves several proteins, including the Ku70/80 heterodimer, DNA-dependent protein kinase catalytic subunit (DNA-PKcs), X-ray cross-complementing protein 4 (XRCC4), XRCC4-like factor (XLF), and ligase IV. These core proteins bind DSBs and ligate the damaged DNA ends. However, details of the structural assembly of these proteins remain unclear. Here, we present cryo-EM structures of NHEJ supercomplexes that are composed of these core proteins and DNA, revealing the detailed structural architecture of this assembly. We describe monomeric and dimeric forms of this supercomplex and also propose the existence of alternate dimeric forms of long-range synaptic complexes. Finally, we show that mutational disruption of several structural features within these NHEJ complexes negatively affects DNA repair.


Assuntos
DNA Ligase Dependente de ATP/ultraestrutura , Enzimas Reparadoras do DNA/ultraestrutura , Proteína Quinase Ativada por DNA/ultraestrutura , Proteínas de Ligação a DNA/ultraestrutura , Complexos Multiproteicos/ultraestrutura , Apoptose/genética , Microscopia Crioeletrônica , Quebras de DNA de Cadeia Dupla , Dano ao DNA/genética , Reparo do DNA por Junção de Extremidades/genética , DNA Ligase Dependente de ATP/genética , Reparo do DNA/genética , Enzimas Reparadoras do DNA/genética , Proteína Quinase Ativada por DNA/genética , Proteínas de Ligação a DNA/genética , Humanos , Autoantígeno Ku/genética , Autoantígeno Ku/ultraestrutura , Complexos Multiproteicos/genética , Fosforilação/genética
14.
J Clin Neurosci ; 91: 209-213, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34373029

RESUMO

A female survival benefit has been described for glioblastoma patients. Recent studies report that the effect of 06-methylguanine-DNA-methyltransferase gene promoter (MGMTp) methylation is only present in female patients. We retrospectively studied sex-based survival, including MGMTp-methylation, in a cohort of 159 uniformly treated isocitrate dehydrogenase wildtype (IDHwt) patients. All patients were treated with temozolomide-based chemoradiotherapy after surgery. Kaplan-Meier survival curves and Cox regression models were used to evaluate overall survival. The study included 59 female (37.1%) and 100 male patients (62.9%). There were no statistically significant differences between sexes concerning demographic, surgical or radiological characteristics. Female patients harbored MGMTp-methylated tumors in 45.8% of cases and males in 33% (P = 0.129). Median overall survival was 13.4 months for men and women alike. After adjustment of survival for age, Karnofsky Performance Score, extent of resection and MGMTp-methylation, sex did not have a significant survival impact. However, MGMTp-methylation proved to be an independent beneficial prognosticator for both sexes, contradicting earlier reports. Several sex-based molecular subtypes of glioblastoma with different response to current treatment may exist explaining conflicting survival results in different patient cohorts. Further research on sex-based differences in IDHwt glioblastoma patients is needed.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Feminino , Glioblastoma/diagnóstico por imagem , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Isocitrato Desidrogenase , Masculino , Prognóstico , Estudos Retrospectivos
15.
Biomolecules ; 11(7)2021 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-34356632

RESUMO

Ubiquitin (Ub) specifically interacts with the Ub-associating domain (UBA) in a proteasomal shuttle factor, while the latter is involved in either proteasomal targeting or self-assembly coacervation. PINK1 phosphorylates Ub at S65 and makes Ub alternate between C-terminally relaxed (pUbRL) and retracted conformations (pUbRT). Using NMR spectroscopy, we show that pUbRL but not pUbRT preferentially interacts with the UBA from two proteasomal shuttle factors Ubqln2 and Rad23A. Yet discriminatorily, Ubqln2-UBA binds to pUb more tightly than Rad23A does and selectively enriches pUbRL upon complex formation. Further, we determine the solution structure of the complex between Ubqln2-UBA and pUbRL and uncover the thermodynamic basis for the stronger interaction. NMR kinetics analysis at different timescales further suggests an indued-fit binding mechanism for pUb-UBA interaction. Notably, at a relatively low saturation level, the dissociation rate of the UBA-pUbRL complex is comparable with the exchange rate between pUbRL and pUbRT. Thus, a kinetic constraint would dictate the interaction between Ub and UBA, thus fine-tuning the functional state of the proteasomal shuttle factors.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Relacionadas à Autofagia/química , Enzimas Reparadoras do DNA/química , Proteínas de Ligação a DNA/química , Proteínas Quinases/química , Ubiquitina/química , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Relacionadas à Autofagia/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Humanos , Ressonância Magnética Nuclear Biomolecular , Ligação Proteica , Domínios Proteicos , Proteínas Quinases/metabolismo , Termodinâmica , Ubiquitina/metabolismo
16.
Am J Surg Pathol ; 45(11): 1516-1526, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34366423

RESUMO

Extraneural metastases of glioblastoma (GBM), although rare, are becoming an increasingly recognized occurrence. Currently, the biological mechanism underlying this rare occurrence is not understood. To explore the potential genomic drivers of extraneural metastasis in GBM, we present the molecular features of 4 extraneural metastatic GBMs, along with a comprehensive review and analysis of previously reported cases that had available molecular characterization. In addition to our 4 cases, 42 patients from 35 publications are reviewed. To compare the molecular profiles between GBM cases with extraneural metastasis and the general GBM population, genomic data from GBM samples in The Cancer Genome Atlas (TCGA) database were also analyzed. We found that 64.5% (20/31) of the cases with extraneural metastasis that were tested for TP53 changes had at least 1 TP53 pathogenic variant detected in either 1 or both primary and metastatic tumors. In contrast, TP53 mutation was significantly less frequent in the unselected GBM from TCGA (22.6%, 56/248) (P=0.000). In addition, O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation was more common in unselected TCGA GBM cases (48.6%, 170/350) than in cases with extraneural metastasis (31.8%, 7/22), although not statistically significant. Although isocitrate dehydrogenase (IDH) mutation is a rare occurrence in high-grade astrocytomas, IDH-mutant grade 4 astrocytomas are at least as likely to metastasize as IDH wild-type GBMs; 3 metastatic cases definitively harbored an IDH1 (p.R132H) mutation in our analysis. Our findings not only provide potential biomarkers for earlier screening of extraneural metastasis, but could also suggest clues to understanding biological mechanisms underlying GBM metastasis, and for the development of therapeutic modalities.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Glioblastoma/genética , Glioblastoma/secundário , Mutação , Proteína Supressora de Tumor p53/genética , Idoso , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Bases de Dados Genéticas , Receptores ErbB/genética , Feminino , Amplificação de Genes , Predisposição Genética para Doença , Humanos , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Regiões Promotoras Genéticas , Estudos Retrospectivos , Proteínas Supressoras de Tumor/genética
17.
Biomed Res Int ; 2021: 5579359, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34373835

RESUMO

Background: Glioma is the most common malignant tumor of the brain in adult patients. The standardized treatment protocol is based on surgical therapy, supplemented with radiotherapy and chemotherapy. However, the prognosis is still unsatisfied. Chemoresistance is one of the most important reason for the poor prognosis of glioma patients. It has confirmed that glioma stem cell (GSC) is one of the reasons for chemoresistance. Methods: In this study, three datasets (GSE23806, COSMIC, and TCGA) were used to perform the analysis to search for the key genes related to GSC, temozolomide (TMZ) resistance, and prognosis. The key gene for further research was selected by reviewing the previous studies. The selected gene investigated the relation between expression levels and clinical characteristics in both TCGA and CGGA dataset. The bioinformatics analysis was performed by Gene Ontology (GO) analysis. The survival analysis was performed by Kaplan-Meier survival analysis. Results: AE binding protein 1 (AEBP1) was selected for further analysis. AEBP1 was overexpressed in GSCs and TMZ resistance cells. In both TCGA and CGGA dataset, the results showed that the expression level of AEBP1 was increased in glioblastoma (GBM) samples, IDH wild-type samples, and MGMT promoter unmethylated samples. Meanwhile, AEBP1 expression was positively related to several GSC markers. GO analysis showed that AEBP1 was related to immune response, cell adhesion, apoptotic process, inflammatory response, positive regulation of cell proliferation, angiogenesis, response to drug, and response to hypoxia. The survival analysis showed that the overexpressed level of AEBP1 was correlated with short survival time in both glioma and GBM patients. Conclusion: In summary, AEBP1 was related with GSC-induced TMZ resistance. Our study showed that AEBP1 might be an oncogene and a new effective therapeutic target for the treatment of glioma.


Assuntos
Neoplasias Encefálicas/mortalidade , Carboxipeptidases/genética , Resistencia a Medicamentos Antineoplásicos , Glioma/mortalidade , Proteínas Repressoras/genética , Regulação para Cima , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Bases de Dados Genéticas , Epigênese Genética , Feminino , Glioma/genética , Humanos , Masculino , Transplante de Neoplasias , Prognóstico , Regiões Promotoras Genéticas , Análise de Sobrevida , Temozolomida , Proteínas Supressoras de Tumor/genética
18.
PLoS Pathog ; 17(8): e1009812, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34343212

RESUMO

MmuPV1 is a useful model for studying papillomavirus-induced tumorigenesis. We used RNA-seq to look for chimeric RNAs that map to both MmuPV1 and host genomes. In tumor tissues, a higher proportion of total viral reads were virus-host chimeric junction reads (CJRs) (1.9‰ - 7‰) than in tumor-free tissues (0.6‰ - 1.3‰): most CJRs mapped to the viral E2/E4 region. Although most of the MmuPV1 integration sites were mapped to intergenic regions and introns throughout the mouse genome, integrations were seen more than once in several genes: Malat1, Krt1, Krt10, Fabp5, Pard3, and Grip1; these data were confirmed by rapid amplification of cDNA ends (RACE)-Single Molecule Real-Time (SMRT)-seq or targeted DNA-seq. Microhomology sequences were frequently seen at host-virus DNA junctions. MmuPV1 infection and integration affected the expression of host genes. We found that factors for DNA double-stranded break repair and microhomology-mediated end-joining (MMEJ), such as H2ax, Fen1, DNA polymerase Polθ, Cdk1, and Plk1, exhibited a step-wise increase and Mdc1 a decrease in expression in MmuPV1-infected tissues and MmuPV1 tumors relative to normal tissues. Increased expression of mitotic kinases CDK1 and PLK1 appears to be correlated with CtIP phosphorylation in MmuPV1 tumors, suggesting a role for MMEJ-mediated DNA joining in the MmuPV1 integration events that are associated with MmuPV1-induced progression of tumors.


Assuntos
Reparo do DNA por Junção de Extremidades , Enzimas Reparadoras do DNA/metabolismo , DNA Viral/genética , Queratinócitos/metabolismo , Papiloma/genética , Papillomaviridae/genética , Infecções por Papillomavirus/genética , Animais , Animais Recém-Nascidos , Quebras de DNA de Cadeia Dupla , Enzimas Reparadoras do DNA/genética , Feminino , Genoma Viral , Recombinação Homóloga , Queratinócitos/virologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Papiloma/virologia , Infecções por Papillomavirus/metabolismo , Infecções por Papillomavirus/virologia , RNA-Seq
19.
CNS Oncol ; 10(3): CNS76, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34378977

RESUMO

Aim: Investigate real-world outcomes and healthcare utilization of patients with glioblastoma multiforme (GBM) related to O6-methylguanine DNA methyltransferase (MGMT) promoter testing and methylation. Patients & methods: US Oncology Network data were analyzed for patients receiving first-line (1L) treatment for GBM. Results: Most patients received 1L radiation with temozolomide. Unadjusted median overall survival (OS) was higher in tested versus untested (median:18.1 vs 11.8 months) and in methylated versus unmethylated (median: 25.5 vs 12.4 months). Untested status, unmethylated MGMT and older age were associated with reduced OS and longer 1L treatment with increased OS. Similar findings were observed for progression-free survival. Utilization was similar between cohorts. Conclusion: In community oncology practices, MGMT methylation and testing were predictive of better survival in GBM.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Idoso , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/terapia , Metilação de DNA , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Dacarbazina/uso terapêutico , Glioblastoma/tratamento farmacológico , Glioblastoma/terapia , Humanos , Estudos Retrospectivos , Proteínas Supressoras de Tumor/genética
20.
Cells ; 10(8)2021 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-34440647

RESUMO

Immune-checkpoint inhibitors (ICIs) play a key role in the treatment of advanced stage colorectal cancer (CRC) patients featuring a deficient DNA mismatch repair (dMMR) system or a high microsatellite instability (MSI-H) profile. However, beyond the established role in CRC patients, ICIs have highly proven efficacy in other solid tumors featuring MSI-H/dMMR status represented by endometrial, gastric, ovarian, prostatic, and pancreatic carcinomas (EC, GC, OC, PrC, and PaC). Our aim was to compare the concordance rates among the Idylla™ MSI test, TapeStation 4200, and immunohistochemical (IHC) analysis in assessing MSI-H/dMMR status in EC, GC, OC, PrC, and PaC patients. The Sanger sequencing-based Titano MSI test was used in discordant cases. One hundred and eighty-five cases (n = 40 PrC, n = 39 GC, n = 38 OC, n = 35 PaC, and n = 33 EC) were retrospectively selected. MMR protein expression was evaluated by IHC. After DNA quality and quantity evaluations, the IdyllaTM and TapeStation 4200 platforms were adopted for the evaluation of MSI status. Remarkably, compared to IHC, the Idylla™ platform achieved a global concordance rate of 94.5% (154/163) for the microsatellite stable (MSS)/proficient MMR (pMMR) cases and 77.3% (17/22) for the MSI-H/dMMR cases. Similarly, a global concordance rate of 91.4% (149/163) and 68.2% (15/22) for MSS/pMMR and MSI-H/dMMR cases was also identified between IHC and the TapeStation 4200 microfluidic system. In addition, a global concordance of 93.1% (148/159) and 69.2% (18/26) for MSS/pMMR and MSI-H/dMMR cases was observed between the Idylla™ and TapeStation 4200 platforms. Discordant cases were analyzed using the Titano MSI kit. Overall, our data pinpointed a central role for molecular techniques in the diagnostic evaluation of dMMR/MSI-H status not only in CRC patients but also in other types of solid tumors.


Assuntos
Reparo de Erro de Pareamento de DNA , Neoplasias do Sistema Digestório/genética , Neoplasias dos Genitais Femininos/genética , Instabilidade de Microssatélites , Neoplasias da Próstata/genética , Biomarcadores Tumorais/análise , Enzimas Reparadoras do DNA/análise , Neoplasias do Sistema Digestório/enzimologia , Neoplasias do Sistema Digestório/patologia , Neoplasias do Endométrio/enzimologia , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Feminino , Neoplasias dos Genitais Femininos/enzimologia , Neoplasias dos Genitais Femininos/patologia , Humanos , Imuno-Histoquímica , Itália , Masculino , Técnicas Analíticas Microfluídicas , Técnicas de Diagnóstico Molecular , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Reação em Cadeia da Polimerase , Valor Preditivo dos Testes , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia , Reprodutibilidade dos Testes , Estudos Retrospectivos , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia
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