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Glioblastoma (GB) is the most aggressive and common type of cancer within the central nervous system (CNS). Despite the vast knowledge of its physiopathology and histology, its etiology at the molecular level has not been completely understood. Thus, attaining a cure has not been possible yet and it remains one of the deadliest types of cancer. Usually, GB is diagnosed when some symptoms have already been presented by the patient. This diagnosis is commonly based on a physical exam and imaging studies, such as computed tomography (CT) and magnetic resonance imaging (MRI), together with or followed by a surgical biopsy. As these diagnostic procedures are very invasive and often result only in the confirmation of GB presence, it is necessary to develop less invasive diagnostic and prognostic tools that lead to earlier treatment to increase GB patients' quality of life. Therefore, blood-based biomarkers (BBBs) represent excellent candidates in this context. microRNAs (miRNAs) are small, non-coding RNAs that have been demonstrated to be very stable in almost all body fluids, including saliva, serum, plasma, urine, cerebrospinal fluid (CFS), semen, and breast milk. In addition, serum-circulating and exosome-contained miRNAs have been successfully used to better classify subtypes of cancer at the molecular level and make better choices regarding the best treatment for specific cases. Moreover, as miRNAs regulate multiple target genes and can also act as tumor suppressors and oncogenes, they are involved in the appearance, progression, and even chemoresistance of most tumors. Thus, in this review, we discuss how dysregulated miRNAs in GB can be used as early diagnosis and prognosis biomarkers as well as molecular markers to subclassify GB cases and provide more personalized treatments, which may have a better response against GB. In addition, we discuss the therapeutic potential of miRNAs, the current challenges to their clinical application, and future directions in the field.
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Glioblastoma , MicroRNAs , Feminino , Humanos , MicroRNAs/genética , Glioblastoma/patologia , Prognóstico , Qualidade de Vida , BiomarcadoresRESUMO
Multi-charged nanoemulsions (NE) were designed to deliver Cannabidiol (CBD), Indocyanine green (ICG), and Protoporphyrin (PpIX) to treat glioblastoma (GBM) through Photodynamic Therapy (PDT). The phase-inversion temperature (PIT) method resulted in a highly stable NE that can be scaled easily, with a six-month shelf-life. We observed the quasi-spherical morphology of the nanoemulsions without any unencapsulated material and that 89% (± 5.5%) of the material was encapsulated. All physicochemical properties were within the expected range for a nanostructured drug delivery system, making these multi-charged nanoemulsions promising for further research and development. NE-PIC (NE-Protoporphyrin + Indocyanine + CBD) was easily internalized on GBM cells after three hours of incubation. Nanoemulsion (NE and NE-PIC) did not result in significant cytotoxicity, even for GBM or non-tumorigenic cell lines (NHF). Phototoxicity was significantly higher for the U87MG cell than the T98G cell when exposed to: visible (430 nm) and infrared (810 nm) laser light, with a difference of about 20%. From 50 mJ.cm-2, the viability of GBM cell lines decreases significantly, ranging from 65% to 85%. The NE-PIC was also effective for inhibiting cell proliferation into a 3D spheroidal GBM cell model, which is promising for mimicking the tumor cell environment. Irradiation at 810 nm was more effective in treating spheroid due to its deeper penetration in complex structures. NE-PIC has the potential as a drug delivery system for photoinactivation and photo diagnostic of GBM cell lines, taking advantage of the versatility of its active components.
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Glioblastoma , Fotoquimioterapia , Humanos , Fotoquimioterapia/métodos , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Fármacos Fotossensibilizantes/farmacologia , Fármacos Fotossensibilizantes/uso terapêutico , Protoporfirinas/metabolismo , Linhagem Celular TumoralRESUMO
Glioblastoma (GBM) is an incurable primary brain tumor with a poor prognosis. Resection, radiation therapy, and temozolomide (TMZ) are insufficient to increase survival, making the treatment limited. Thus, the search for more effective and specific treatments is essential, making plants a promising source for elucidating new anti-glioblastoma compounds. Accordingly, this study investigated the effects of four fractions of hexane and ethyl acetate extract of Annona coriacea Mart., enriched with acetogenins, against GBM cell lines. All four fractions were selectively cytotoxic to GBM cells when compared to TMZ. Moreover, A. coriacea fractions delayed cell migration; reduced cytoplasmic projections, the metalloproteinase 2 (MMP-2) activity; and induced morphological changes characteristic of necroptosis, possibly correlated with the increase in receptor-interacting protein kinase 1 and 3 (RIP-1 and RIP-3), apoptosis-inducing factor (AIF), and the non-activation of cleaved caspase 8. The present findings reinforce that fractions of A. coriacea Mart. should be considered for more studies focusing treatment of GBM.
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Annona , Neoplasias Encefálicas , Glioblastoma , Humanos , Metaloproteinase 2 da Matriz , Acetogeninas/farmacologia , Necroptose , Glioblastoma/metabolismo , Temozolomida/farmacologia , Linhagem Celular Tumoral , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Resistencia a Medicamentos Antineoplásicos , ApoptoseRESUMO
Glioblastoma (GBM) is an aggressive brain cancer associated with poor overall survival. The metabolic status and tumor microenvironment of GBM cells have been targeted to improve therapeutic strategies. TLR4 is an important innate immune receptor capable of recognizing pathogens and danger-associated molecules. We have previously demonstrated the presence of TLR4 in GBM tumors and the decreased viability of the GBM tumor cell line after lipopolysaccharide (LPS) (TLR4 agonist) stimulation. In the present study, metformin (MET) treatment, used in combination with temozolomide (TMZ) in two GBM cell lines (U87MG and A172) and stimulated with LPS was analyzed. MET is a drug widely used for the treatment of diabetes and has been repurposed for cancer treatment owing to its anti-proliferative and anti-inflammatory actions. The aim of the study was to investigate MET and LPS treatment in two GBM cell lines with different metabolic statuses. MET treatment led to mitochondrial respiration blunting and oxidative stress with superoxide production in both cell lines, more markedly in U87MG cells. Decreased cell viability after MET + TMZ and MET + LPS + TMZ treatment was observed in both cell lines. U87MG cells exhibited apoptosis after MET + LPS + TMZ treatment, promoting increased ER stress, unfolded protein response, and BLC2 downregulation. LPS stimulation of U87MG cells led to upregulation of SOD2 and genes related to the TLR4 signaling pathway, including IL1B and CXCL8. A172 cells attained upregulated antioxidant gene expression, particularly SOD1, TXN and PRDX1-5, while MET treatment led to cell-cycle arrest. In silico analysis of the TCGA-GBM-RNASeq dataset indicated that the glycolytic plurimetabolic (GPM)-GBM subtype had a transcriptomic profile which overlapped with U87MG cells, suggesting GBM cases exhibiting this metabolic background with an activated inflammatory TLR4 pathway may respond to MET treatment. For cases with upregulated CXCL8, coding for IL8 (a pro-angiogenic factor), combination treatment with an IL8 inhibitor may improve tumor growth control. The A172 cell line corresponded to the mitochondrial (MTC)-GBM subtype, where MET plus an antioxidant inhibitor, such as anti-SOD1, may be indicated as a combinatory therapy.
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PIMREG expression strongly correlates with cellular proliferation in both malignant and normal cells. Throughout embryo development, PIMREG expression is prominent in the central nervous system. Recent studies have described elevated PIMREG expression in different types of tumors, which correlates with patient survival and tumor aggressiveness. Given the emerging significance of PIMREG in carcinogenesis and its putative role in the context of the nervous system, we investigated the expression and function of PIMREG in gliomas, the most common primary brain tumors. We performed an extensive analysis of PIMREG expression in tumors samples from glioma patients. We then assessed the effects of PIMREG silencing and overexpression on the sensitivity of glioblastoma cell lines treated with genotoxic agents commonly used for treating patients and assessed for treatment response, proliferation and migration. Our analysis shows that glioblastoma exhibits the highest levels of PIMREG expression among all cancers analyzed and that elevated PIMREG expression is a biomarker for glioma progression and patient outcome. Moreover, PIMREG is induced by genotoxic agents, and its silencing renders glioblastoma cells sensitive to temozolomide treatment and affects ATR- and ATM-dependent signaling. Our data demonstrate that PIMREG is involved in DNA damage response and temozolomide resistance of glioblastoma cells and further supports a role for PIMREG in tumorigenesis.
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Glioblastoma , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Linhagem Celular Tumoral , Dano ao DNA , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Temozolomida/farmacologia , Temozolomida/uso terapêuticoRESUMO
We report clinical, serologic, and immunogenetic studies of a set of monozygotic male twin patients who develop autoimmune thyroiditis and vitiligo associated with the HLA-DRB1*04-DQB1*03:02 and HLA-DRB1*03-DQB1*0201 haplotypes. The patients had detectable anti-thyroid and anti-melanocyte autoantibodies. A critical review is presented regarding the role of MHC II molecules linked to clinical manifestations of various autoimmune diseases displayed in a single patient, as is the case in the twin patients reported here.
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Malignant cells are commonly characterised by being capable of invading tissue, growing self-sufficiently and uncontrollably, being insensitive to apoptosis induction and controlling their environment, for example inducing angiogenesis. Amongst them, a subpopulation of cancer cells, called cancer stem cells (CSCs) shows sustained replicative potential, tumor-initiating properties and chemoresistance. These characteristics make CSCs responsible for therapy resistance, tumor relapse and growth in distant organs, causing metastatic dissemination. For these reasons, eliminating CSCs is necessary in order to achieve long-term survival of cancer patients. New insights in cancer metabolism have revealed that cellular metabolism in tumors is highly heterogeneous and that CSCs show specific metabolic traits supporting their unique functionality. Indeed, CSCs adapt differently to the deprivation of specific nutrients that represent potentially targetable vulnerabilities. This review focuses on three of the most aggressive tumor types: pancreatic ductal adenocarcinoma (PDAC), hepatocellular carcinoma (HCC) and glioblastoma (GBM). The aim is to prove whether CSCs from different tumour types share common metabolic requirements and responses to nutrient starvation, by outlining the diverse roles of glucose and amino acids within tumour cells and in the tumour microenvironment, as well as the consequences of their deprivation. Beyond their role in biosynthesis, they serve as energy sources and help maintain redox balance. In addition, glucose and amino acid derivatives contribute to immune responses linked to tumourigenesis and metastasis. Furthermore, potential metabolic liabilities are identified and discussed as targets for therapeutic intervention.
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Glioblastoma (GBM) is the most lethal and frequent type of brain tumor, leading patients to death in approximately 14 months after diagnosis. GBM treatment consists in surgical removal followed by radio and chemotherapy. However, tumors commonly relapse and the treatment promotes only a slight increase in patient survival. Thus, uncovering the cellular mechanisms involved in GBM resistance is of utmost interest, and the use of cell lines has been shown to be an extremely important tool. In this work, the exploration of RNAseq data from different GBM cell lines revealed different expression signatures, distinctly correlated with the behavior of GBM cell lines regarding proliferation indexes and radio-resistance. U87MG and U138MG cells, which presented expressively reduced proliferation and increased radio-resistance, showed a particular expression signature encompassing enrichment in many extracellular matrix (ECM) and receptor genes. Contrasting, U251MG and T98G cells, that presented higher proliferation and sensibility to radiation, exhibited distinct signatures revealing consistent enrichments for DNA repair processes and although several genes from the ECM-receptor pathway showed up-regulation, enrichments for this pathway were not detected. The ECM-receptor is a master regulatory pathway that is known to impact several cellular processes including: survival, proliferation, migration, invasion, and DNA damage signaling and repair, corroborating the associations we found. Furthermore, searches to The Cancer Genome Atlas (TCGA) repository revealed prognostic correlations with glioma patients for the majority of genes highlighted in the signatures and led to the identification of 31 ECM-receptor genes individually correlated with radiation responsiveness. Interestingly, we observed an association between the number of upregulated genes and survivability greater than 5 years after diagnosis, where almost all the patients that presented 21 or more upregulated genes were deceased before 5 years. Altogether our findings suggest the clinical relevance of ECM-receptor genes signature found here for radiotherapy decision and as biomarkers of glioma prognosis.
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Internalized homonegativity results from the acceptance of negative attitudes about one's same-sex orientation, which has negative consequences for the health of gay, bisexual and other men who have sex with men (GBM). We translated the 7-item Reactions to Homosexuality Scale (RHS) to Brazilian Portuguese and assessed its factor structure, validity and reliability. The first step included the translation, back-translation, evaluation, peer review, and pre-testing of the scale. Then, we piloted the scale in two convenience samples of adult Brazilians recruited online during October 2019 and February to March 2020 through advertisements on Grindr and Hornet, respectively. The largest sample was randomly split into two groups for exploratory factor analysis (EFA) then confirmatory factor analysis (CFA). Criterion and construct validity were assessed via correlations between scale scores and study variables. A total of 5573 GBM (sample 1: 218; sample 2: 5355) completed the RHS. EFA (N = 2652) yielded two eigenvalues greater than one (Factor 1: 3.5 and Factor 2: 1.1). A one-factor solution provided the most interpretable model based on examination of scree plot and item factor loadings (χ2(14) = 1373.1, p < 0.001; CFI = 0.89; TLI = 0.84; RMSEA = 0.19; SRMS = 0.09). Though one-factor CFA showed moderate fit, freeing errors terms to covary, based on item content and interpretation, significantly improved model fit (χ2(12) = 309.1, p < .001; CFI = 0.97; TLI = 0.96; RMSEA = 0.09; SRMR = 0.02). As hypothesized, men who did not self-identify as gay (mean score 17.9 compared to those self-identifying as gay: 11.8) and men who reported no sex with men in the past 6 months (mean score 12.6 compared to those who reported sex with men: 10.6) scored higher reflecting higher internalized homonegativity. The RHS was effectively translated and validated in Brazilian Portuguese and can be used to evaluate the role of internalized homonegativity on GBM's health, as well as its impact on the uptake of HIV prevention technologies.
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Homossexualidade Masculina , Minorias Sexuais e de Gênero , Adulto , Bissexualidade , Brasil , Humanos , Masculino , Reprodutibilidade dos Testes , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Valid and reliable instruments are needed to measure the multiple dimensions of perceived risk. The Perceived Risk of HIV Scale is an 8-item measure that assesses how people think and feel about their risk of infection. We set out to perform a cross-cultural adaptation of the scale to Brazilian Portuguese among key populations (gay, bisexual and other men who have sex with men and transgender/non-binary) and other populations (cisgender heterosexual men and cisgender women). METHODS: Methodological study with cross-sectional design conducted online during October/2019 (key populations [sample 1] and other populations) and February-March/2020 (key populations not on pre-exposure prophylaxis [sample 2]). Cross-cultural adaptation of the Perceived Risk of HIV Scale followed Beaton et al. 2000 guidelines and included confirmatory factor analysis, differential item functioning (DIF) using the Multiple-Indicator Multiple-Cause model, and concurrent validity to verify if younger individuals, those ever testing for HIV, and engaging in high-risk behaviors had higher scores on the scale. RESULTS: 4342 participants from key populations (sample 1 = 235; sample 2 = 4107) and 155 participants from other populations completed the measure. We confirmed the single-factor structure of the original measure (fit indices for sample 1 plus other populations: CFI = 0.98, TLI = 0.98, RMSEA = 0.07; sample 2 plus other populations: CFI = 0.97, TLI = 0.95, RMSEA = 0.09). For the comparisons between key populations and other populations, three items (item 2: "I worry about getting infected with HIV", item 4: "I am sure I will not get infected with HIV", and item 8: "Getting HIV is something I have") exhibited statistically significant DIF. Items 2 and 8 were endorsed at higher levels by key populations and item 4 by other populations. However, the effect of DIF on overall scores was negligible (0.10 and 0.02 standard deviations for the models with other populations plus sample 1 and 2, respectively). Those ever testing for HIV scored higher than those who never tested (p < .001); among key populations, those engaging in high-risk behaviors scored higher than those reporting low-risk. CONCLUSION: The Perceived Risk of HIV Scale can be used among key populations and other populations from Brazil.
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Comparação Transcultural , Etnicidade/psicologia , Infecções por HIV/psicologia , Homossexualidade Masculina/psicologia , Medição de Risco/normas , Minorias Sexuais e de Gênero/psicologia , Inquéritos e Questionários/normas , Pessoas Transgênero/psicologia , Adolescente , Adulto , Brasil/epidemiologia , Estudos Transversais , Etnicidade/estatística & dados numéricos , Análise Fatorial , Feminino , Infecções por HIV/epidemiologia , Homossexualidade Masculina/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Medição de Risco/métodos , Minorias Sexuais e de Gênero/estatística & dados numéricos , Pessoas Transgênero/estatística & dados numéricos , Adulto JovemRESUMO
Epithelial-mesenchymal transition (EMT) is an essential mechanism contributing to glioblastoma multiforme (GBM) progression, the most common and malignant brain tumor. EMT is induced by signaling pathways that crosstalk and regulate an intricate regulatory network of transcription factors. It has been shown that downstream components of 17ß-estradiol (E2) and transforming growth factor ß (TGF-ß) signaling pathways crosstalk in estrogen-sensitive tumors. However, little is known about the interaction between the E2 and TGF-ß signaling components in brain tumors. We have investigated the relationship between E2 and TGF-ß signaling pathways and their effects on EMT induction in human GBM-derived cells. Here, we showed that E2 and TGF-ß negatively regulated the expression of estrogen receptor α (ER-α) and Smad2/3. TGF-ß induced Smad2 phosphorylation and its subsequent nuclear translocation, which E2 inhibited. Both TGF-ß and E2 induced cellular processes related to EMT, such as morphological changes, actin filament reorganization, and mesenchymal markers (N-cadherin and vimentin) expression. Interestingly, we found that the co-treatment of E2 and TGF-ß blocked EMT activation. Our results suggest that E2 and TGF-ß signaling pathways interact through ER-α and Smad2/3 mediators in cells derived from human GBM and inhibit EMT activation induced by both factors alone.
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BACKGROUND: Glioblastoma is the most frequent and high-grade adult malignant central nervous system tumor. The prognosis is still poor despite the use of combined therapy involving maximal surgical resection, radiotherapy, and chemotherapy. Metabolic reprogramming currently is recognized as one of the hallmarks of cancer. Glutamine metabolism through glutaminolysis has been associated with tumor cell maintenance and survival, and with antioxidative stress through glutathione (GSH) synthesis. METHODS: In the present study, we analyzed the glutaminolysis-related gene expression levels in our cohort of 153 astrocytomas of different malignant grades and 22 non-neoplastic brain samples through qRT-PCR. Additionally, we investigated the protein expression profile of the key regulator of glutaminolysis (GLS), glutamate dehydrogenase (GLUD1), and glutamate pyruvate transaminase (GPT2) in these samples. We also investigated the glutathione synthase (GS) protein profile and the GSH levels in different grades of astrocytomas. The differential gene expressions were validated in silico on the TCGA database. RESULTS: We found an increase of glutaminase isoform 2 gene (GLSiso2) expression in all grades of astrocytoma compared to non-neoplastic brain tissue, with a gradual expression increment in parallel to malignancy. Genes coding for GLUD1 and GPT2 expression levels varied according to the grade of malignancy, being downregulated in glioblastoma, and upregulated in lower grades of astrocytoma (AGII-AGIII). Significant low GLUD1 and GPT2 protein levels were observed in the mesenchymal subtype of GBM. CONCLUSIONS: In glioblastoma, particularly in the mesenchymal subtype, the downregulation of both genes and proteins (GLUD1 and GPT2) increases the source of glutamate for GSH synthesis and enhances tumor cell fitness due to increased antioxidative capacity. In contrast, in lower-grade astrocytoma, mainly in those harboring the IDH1 mutation, the gene expression profile indicates that tumor cells might be sensitized to oxidative stress due to reduced GSH synthesis. The measurement of GLUD1 and GPT2 metabolic substrates, ammonia, and alanine, by noninvasive MR spectroscopy, may potentially allow the identification of IDH1mut AGII and AGIII progression towards secondary GBM.
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In Brazil, pre-exposure prophylaxis (PrEP) is currently available for gay, bisexual, and other men who have sex with men. As PrEP use depends on an individual's perceived risk, we explored pathways by which potentially modifiable behaviors lead to high perceived HIV risk. Using online surveys (N = 16,667), we conducted a path analysis on the basis of ordered sequences of multivariate logistic regressions. High perceived HIV risk was low (26.3%) compared to condomless receptive anal sex (41.4%). While younger age increased the odds of binge drinking and of condomless receptive anal sex, it was associated with decreased odds of high perceived HIV risk. In contrast, use of stimulants increased the odds of condomless receptive anal sex and of high perceived HIV risk. Our results suggest that binge drinking and use of stimulants are key points in different pathways to high-risk sexual behavior and may lead to different perceptions of HIV risk.
RESUMEN: En Brasil, la profilaxis previa a la exposición (PrEP) está disponible actualmente para hombres homosexuales, bisexuales y otros hombres que tienen sexo con hombres. Como el uso de PrEP depende del riesgo percibido de una persona, exploramos vías por las cuales los comportamientos potencialmente modificables conducen a un alto riesgo percibido de VIH. Utilizando datos de encuestas en línea (N = 16.667), realizamos un análisis de ruta sobre la base de secuencias ordenadas de regresiones logísticas multivariadas. El alto riesgo percibido de VIH fue bajo (26,3%) en comparación con el sexo anal receptivo sin condón (41,4%). La edad más joven aumentó las probabilidades de consumo de alcohol en exceso y del sexo anal receptivo sin condón, todavía se asoció con una menor probabilidad de alta percepción de riesgo sobre VIH. Sin embargo, el uso de estimulantes aumentó las probabilidades de tener sexo anal receptivo sin condón y de un alto riesgo percibido de VIH. Nuestros resultados sugieren que el consumo excesivo de alcohol y el uso de estimulantes son puntos clave en diferentes vías de conductas sexuales de alto riesgo y pueden llevar a diferentes percepciones del riesgo de VIH.
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Consumo Excessivo de Bebidas Alcoólicas/epidemiologia , Preservativos/estatística & dados numéricos , Infecções por HIV/prevenção & controle , Homossexualidade Masculina/estatística & dados numéricos , Transtornos Relacionados ao Uso de Substâncias/psicologia , Adolescente , Adulto , Consumo Excessivo de Bebidas Alcoólicas/complicações , Brasil/epidemiologia , Estudos Transversais , Infecções por HIV/epidemiologia , Homossexualidade Masculina/psicologia , Humanos , Masculino , Profilaxia Pré-Exposição , Comportamento Sexual , Parceiros Sexuais , Transtornos Relacionados ao Uso de Substâncias/epidemiologiaRESUMO
PURPOSE: Glioblastoma multiforme (GBM) represents the most common and the most malignant type of brain tumor. Cell division cycle 6 (CDC6), a gene associated with DNA replication initiation, has been proven to be associated with the prognosis of multiple tumors. In this study, we aim to explore the association between CDC6 expression and GBM carcinogenesis and prognosis. METHODS: CDC6 expression in normal cells and GBM cells was explored by analyzing TCGA dataset, as well as by RT-PCR and western blot methods. Survival analysis was performed by the Kaplan-Meier method. Multivariate Cox-regression analysis was adopted to estimate the independence of CDC6 as a GBM prognostic factor. RESULTS AND CONCLUSIONS: Elevated CDC6 levels in GBM tumor tissues compared with those in normal brain tissues were illustrated by analyzing the gene expression profiles from TCGA dataset, and confirmed by RT-PCR and western blot assays in GBM tumor and normal human astrocyte cell lines. Kaplan-Meier analysis indicated the negative influence of high CDC6 expression on GBM overall survival (OS) probability and days to progression (D2P) after initial treatment, but not on days to recurrence (D2R) after initial treatment. Multivariate Cox regression analysis showed CDC6 as an independent signature marker gene for GBM prognosis. In addition, the combination of CDC6 mRNA expression and CpG island methylator phenotype (CIMP) could sensitively predict 3-year OS and D2P. In conclusion, our study uncovered the role of CDC6 in GBM carcinogenesis and prognosis for the first time, which could shed new light on GBM diagnosis and treatment.
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Neoplasias Encefálicas/genética , Proteínas de Ciclo Celular/genética , Glioblastoma/genética , Proteínas Nucleares/genética , Western Blotting , Encéfalo/metabolismo , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidade , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Ilhas de CpG/genética , Bases de Dados Genéticas , Feminino , Expressão Gênica , Glioblastoma/metabolismo , Glioblastoma/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/metabolismo , Prognóstico , Modelos de Riscos Proporcionais , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sobrevida , Transcriptoma , Regulação para CimaRESUMO
Aim: Human Leukocyte Antigen-G (HLA-G) is a non-classical class I molecule that is involved in maternal-fetal immunotolerance. In cancer, this molecule contributes to the tumor escape. The aim of this study was to evaluate the 14 bp In/Del and +3142 C > G polymorphisms of the HLA-G 3' UTR and its relation with plasma and tissue HLA-G expression in patients with grade IV (high-grade) and grade I/II (low-grade) gliomas and controls.Patients and methods: Peripheral blood and tumor biopsies were collected from 85 patients with gliomas and blood samples from 94 controls. Polymorphisms were analyzed from blood DNA. Soluble HLA-G (sHLA-G) was measured by ELISA in plasma of the subjects and the tissue expression by immunohistochemistry on patient's tissue.Results: Higher levels of sHLA-G were observed in grade IV gliomas patients than in controls (p < 0.0001). In grade IV patients, the heterozygous 14pb In/Del, +3142 C/G genotypes and Del/C*In/G haplotype were associated with higher sHLA-G levels (p < 0.0001) when compared with controls. GBM patients were stratified into high and low sHLA-G expression and an association was found between +3142 C allele and high sHLA-G plasmatic levels (p = 0.0095). Tissue HLA-G immunolabel was higher in high-grade than low-grade gliomas (p = 0.0033).Conclusion: This was the first study evaluating HLA-G 3' UTR polymorphisms and expression in patients with gliomas. The 14 bp In/Del and +3142 C/G genotypes and haplotypes showed high influence over sHLA-G expression, suggesting a heterozygous advantage in the tumor context and may contribute to a worse prognosis in glioma patients.
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Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Glioma/genética , Glioma/metabolismo , Antígenos HLA-G/sangue , Regiões 3' não Traduzidas , Adulto , Mapeamento Encefálico , Criança , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
RESUMEN Una vez más en medicina interna no podemos, aún, prescindir de los métodos invasivos para alcanzar un diagnóstico. Los avances diarios en el hallazgo de nuevas herramientas paraclínicas no permiten reemplazar aquellos métodos de certeza como la anatomía patológica. El caso presentado es una muestra de ello. Se trata de una mujer de 27 años de edad, con antecedente de tiroiditis de Hashimoto que consulta por presentar severo deterioro de la función renal asociado a oligoanuria. Realizamos una revisión del tratamiento de las glomerulonefritis rápidamente progresivas por anticuerpos antimembrana basal glomerular, serológicamente negativas.
ABSTRACT Once again in internal medicine we cannot do a diagnosis without invasive methods. Daily advances in the finding of new paraclinical tools do not allow the replacement of certain methods such as pathological anatomy. The case presented is a sample of this. This is a 27-year-old woman with a history of Hashimoto's thyroiditis who consults for presenting severe impairment of kidney function associated with oligoanuria. We performed a review of the treatment of the rapidly progressive glomerulonephritis for serologically negative anti-GBM antibodies.
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BACKGROUND: Minimally invasive procedures are gaining widespread acceptance in difficult-to-access brain tumor treatment. Stereotactic radiosurgery (SRS) is the preferred choice, however, laser interstitial thermal therapy (LITT) has emerged as a tumor cytoreduction technique. The present meta-analysis compared current SRS therapy with LITT in brain tumors. METHODS: A search was performed in Lilacs, PubMed, and Cochrane database. Patient's demographics, tumor location, therapy used, Karnofsky performance status score before treatment, and patient's outcome (median overall survival, progression-free survival, and adverse events) data were extracted from studies. The risk of bias was assessed by Cochrane collaboration tool. RESULTS: Twenty-five studies were included in this meta-analysis. LITT and SRS MOS in brain metastasis patients were 12.8 months' versus 9.8 months (ranges 9.3-16.3 and 8.3-9.8; P = 0.02), respectively. In a combined comparison of adverse effects among LITT versus SRS in brain metastasis, we found 15% reduction in absolute risk difference (-0.16; 95% confidence interval P < 0.0001). CONCLUSION: We could not state that LITT treatment is an optimal alternative therapy for difficult-to-access brain tumors due to the lack of systematic data that were reported in our pooled studies. However, our results identified a positive effect in lowering the absolute risk of adverse events compared with SRS therapy. Therefore, randomized trials are encouraged to ascertain LITT role, as upfront or postoperative/post-SRS therapy for brain tumor treatment.
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BACKGROUND: The relationship between glioblastoma (GBM) and fatty acid metabolism could be the key to elucidate more effective therapeutic targets. 15-lipoxygenase-1 (15-LOX), a linolenic acid and arachidonic acid metabolizing enzyme, induces both pro- and antitumorigenic effects in different cancer types. Its role in glioma activity has not yet been clearly described. The objective of this study was to identify the influence of 15-LOX and its metabolites on glioblastoma cell activity. METHODS: GBM cell lines were examined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to identify 15-LOX metabolites. GBM cells treated with 15-LOX metabolites, 13-hydroxyoctadecadeinoic acid (HODE) and 9-HODE, and two 15-LOX inhibitors (luteolin and nordihydroguaiaretic acid) were also examined. Dose response/viability curves, RT-PCRs, flow cytometry, migration assays, and zymograms were performed to analyze GBM growth, migration, and invasion. RESULTS: Higher quantities of 13-HODE were observed in five GBM cell lines compared to other lipids analyzed. Both 13-HODE and 9-HODE increased cell count in U87MG. 15-LOX inhibition decreased migration and increased cell cycle arrest in the G2/M phase. CONCLUSION: 15-LOX and its linoleic acid (LA)-derived metabolites exercise a protumorigenic influence on GBM cells in vitro. Elevated endogenous levels of 13-HODE called attention to the relationship between linoleic acid metabolism and GBM cell activity.
Assuntos
Araquidonato 15-Lipoxigenase/metabolismo , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Inibidores de Lipoxigenase/farmacologia , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Glioma/tratamento farmacológico , Glioma/metabolismo , Humanos , Ácido Linoleico/metabolismo , Ácidos Linoleicos/metabolismo , Ácidos Linoleicos Conjugados/metabolismoRESUMO
Glioblastoma (GBM) is one of the most malignant primary intracranial neoplasms. This review aims to summarize the treatment of elderly patients with newly diagnosed GBM, with a focus on the radiation therapy (RT) approach. The available literature was reviewed, and we describe the most significant results relating to the post-operative approach of elderly GBM patients. Age limitations in randomized phase III studies have restricted the inclusion of elderly patients, and consequently, limited the generalizability of their results to this patient subset. Chronological age should not prohibit the best treatment, but instead, treatment decisions should consider patient functional status. RT showed efficacy and safety in the elderly population, without compromising quality of life. Hypofractionated RT is not inferior to standard RT. Reduction of overall RT schedule length mitigates the difficulties faced by elderly patients, improving treatment adherence. The addition of both concomitant and adjuvant temozolomide to standard RT is superior to either modality alone and should be the treatment of choice in the subset of patients with good/very good prognosis. It is reasonable to offer hypofractionated RT or temozolomide alone for poor prognosis, and best supportive care (BSC) for very poor prognosis elderly GBM patients. Although combined modality treatment is well established for the management of the good prognosis population, different RT schemes require further investigation with randomized controlled trials to determine the best regimen. A robust analysis of the molecular signatures of GBM in elderly patients might reveal opportunities for clinical protocol modifications to customize management in this group of patients.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Idoso , Neoplasias Encefálicas/radioterapia , Terapia Combinada , Glioblastoma/radioterapia , Humanos , Qualidade de Vida , TemozolomidaRESUMO
The mesenchymal phenotype of glioblastoma multiforme (GBM), the most frequent and malignant brain tumor, is associated with the worst prognosis. The epithelial-mesenchymal transition (EMT) is a cell plasticity mechanism involved in GBM malignancy. In this study, we determined 17ß-estradiol (E2)-induced EMT by changes in cell morphology, expression of EMT markers, and cell migration and invasion assays in human GBM-derived cell lines. E2 (10 nM) modified the shape and size of GBM cells due to a reorganization of actin filaments. We evaluated EMT markers expression by RT-qPCR, Western blot, and immunofluorescence.We found that E2 upregulated the expression of the mesenchymal markers, vimentin, and N-cadherin. Scratch and transwell assays showed that E2 increased migration and invasion of GBM cells. The estrogen receptor-α (ER-α)-selective agonist 4,4',4''-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT, 10 nM) affected similarly to E2 in terms of the expression of EMT markers and cell migration, and the treatment with the ER-α antagonist methyl-piperidino-pyrazole (MPP, 1 µM) blocked E2 and PPT effects. ER-ß-selective agonist diarylpropionitrile (DNP, 10 nM) and antagonist 4-[2-phenyl-5,7-bis(trifluoromethyl)pyrazole[1,5-a]pyrimidin-3-yl]phenol (PHTPP, 1 µM) showed no effects on EMT marker expression. These data suggest that E2 induces EMT activation through ER-α in human GBM-derived cells.