RESUMO
Glioblastoma is the most prevalent and malignant brain tumor identified in adults. Surgical resection followed by radiotherapy and chemotherapy, mainly with temozolomide (TMZ), is the chosen treatment for this type of tumor. However, the average survival of patients is around 15 months. Novel approaches to glioblastoma treatment are greatly needed. Here, we aimed to investigate the anti-glioblastoma effect of the combination of matteucinol (Mat) (dihydroxyflavanone derived from Miconia chamissois Naudin) with the chemotherapeutic TMZ in vitro using tumor (U-251MG) and normal astrocyte (NHA) cell lines and in vivo using the chick embryo chorioallantoic membrane (CAM) assay. The combination was cytotoxic and selective for tumor cells (28 µg/mL Mat and 9.71 µg/mL TMZ). Additionally, the combination did not alter cell adhesion but caused morphological changes characteristic of apoptosis in vitro. Notably, the combination was also able to reduce tumor growth in the chick embryo model (CAM assay). The docking results showed that Mat was the best ligand to the cell death membrane receptor TNFR1 and to TNFR1/TMZ complex, suggesting that these two molecules may be working together increasing their potential. In conclusion, Mat-TMZ can be a good candidate for pharmacokinetic studies in view of clinical use for the treatment of glioblastoma.
Assuntos
Glioblastoma , Receptores Tipo I de Fatores de Necrose Tumoral , Animais , Apoptose , Linhagem Celular Tumoral , Proliferação de Células , Embrião de Galinha , Cromonas , Biologia Computacional , Glioblastoma/tratamento farmacológico , Humanos , Temozolomida/farmacologia , Temozolomida/uso terapêuticoRESUMO
Glioblastoma is the most prevalent and malignant brain tumor identified in adults. Surgical resection followed by radiotherapy and chemotherapy, mainly with temozolomide (TMZ), is the chosen treatment for this type of tumor. However, the average survival of patients is around 15 months. Novel approaches to glioblastoma treatment are greatly needed. Here, we aimed to investigate the anti-glioblastoma effect of the combination of matteucinol (Mat) (dihydroxyflavanone derived from Miconia chamissois Naudin) with the chemotherapeutic TMZ in vitro using tumor (U-251MG) and normal astrocyte (NHA) cell lines and in vivo using the chick embryo chorioallantoic membrane (CAM) assay. The combination was cytotoxic and selective for tumor cells (28 μg/mL Mat and 9.71 μg/mL TMZ). Additionally, the combination did not alter cell adhesion but caused morphological changes characteristic of apoptosis in vitro. Notably, the combination was also able to reduce tumor growth in the chick embryo model (CAM assay). The docking results showed that Mat was the best ligand to the cell death membrane receptor TNFR1 and to TNFR1/TMZ complex, suggesting that these two molecules may be working together increasing their potential. In conclusion, Mat-TMZ can be a good candidate for pharmacokinetic studies in view of clinical use for the treatment of glioblastoma.
RESUMO
Metastasis remains the most common cause of death in cancer patients. Inhibition of metalloproteinases (MMPs) is an interesting approach to cancer therapy because of their role in the degradation of extracellular matrix (ECM), cell-cell, and cell-ECM interactions, modulating key events in cell migration and invasion. Herein, we show the cytotoxic and antimetastatic effects of the third fraction (FR3) from Bauhinia variegata candida (Bvc) stem on human cervical tumor cells (HeLa) and human peripheral blood mononuclear cells (PBMCs). FR3 inhibited MMP-2 and MMP-9 activity, indicated by zymogram. This fraction was cytotoxic to HeLa cells and noncytotoxic to PBMCs and decreased HeLa cell migration and invasion. FR3 is believed to stimulate extrinsic apoptosis together with necroptosis, assessed by western blotting. FR3 inhibited MMP-2 activity in the HeLa supernatant, differently from the control. The atomic mass spectrometry (ESI-MS) characterization suggested the presence of glucopyranosides, D-pinitol, fatty acids, and phenolic acid. These findings provide insight suggesting that FR3 contains components with potential tumor-selective cytotoxic action in addition to the action on the migration of tumor cells, which may be due to inhibition of MMPs.
Assuntos
Bauhinia/química , Caspase 3/metabolismo , Morte Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Extratos Vegetais/farmacologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Citotoxinas/farmacologia , Ácidos Graxos/farmacologia , Células HeLa , Humanos , Hidroxibenzoatos/farmacologia , Inositol/análogos & derivados , Inositol/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Invasividade Neoplásica/prevenção & controle , Transdução de Sinais/efeitos dos fármacosRESUMO
Cofilin-1 (CFL1), a small protein of 18 kDa, has been studied as a biomarker due to its involvement in tumor cell migration and invasion. Our aim was to evaluate CFL1 as an indicator of malignancy and aggressiveness in sputum samples. CFL1 was analyzed by ELISA immunoassay in the sputum of 73 lung cancer patients, 13 cancer-free patients, and 6 healthy volunteers. Statistical analyses included ANOVA, ROC curves, Spearman correlation, and logistic regression. Sputum CFL1 levels were increased in cancer patients compared to cancer-free patients and volunteers (P<0.05). High expression of sputum CFL1 was correlated to T4 stage (P=0.01) and N stage (P=0.03), tobacco history (P=0.01), and squamous cell carcinoma histologic type (P=0.04). The accuracy of sputum CFL1 in discriminating cancer patients from cancer-free patients and healthy volunteers were 0.78 and 0.69, respectively. CFL1 at a cut-off value of 415.25 pg/mL showed sensitivity/specificity of 0.80/0.70 in differentiating between healthy volunteers and cancer patients. Sputum CFL1 was also able to identify cancer-free patients from patients with lung cancer. The AUC was 0.70 and, at a cut-off point ≥662.63 pg/mL, we obtained 60% sensitivity and 54% specificity. Logistic regression analysis controlled for tobacco history, histologic types, and N stage showed that cancer cell-associated CFL1 was an independent predictor of death. Smoker patients with squamous cell carcinoma, lymph node metastasis and sputum CFL1>1.475 pg/mL showed augmented chance of death, suggesting lung cancer aggressiveness. CFL1 presented diagnostic value in detecting lung cancer and was associated to tumor aggressiveness.
Assuntos
Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/química , Cofilina 1/análise , Neoplasias Pulmonares/química , Escarro/química , Adulto , Idoso , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Proliferação de Células , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Prognóstico , Curva ROC , Sensibilidade e EspecificidadeRESUMO
Cofilin-1 (CFL1), a small protein of 18 kDa, has been studied as a biomarker due to its involvement in tumor cell migration and invasion. Our aim was to evaluate CFL1 as an indicator of malignancy and aggressiveness in sputum samples. CFL1 was analyzed by ELISA immunoassay in the sputum of 73 lung cancer patients, 13 cancer-free patients, and 6 healthy volunteers. Statistical analyses included ANOVA, ROC curves, Spearman correlation, and logistic regression. Sputum CFL1 levels were increased in cancer patients compared to cancer-free patients and volunteers (P<0.05). High expression of sputum CFL1 was correlated to T4 stage (P=0.01) and N stage (P=0.03), tobacco history (P=0.01), and squamous cell carcinoma histologic type (P=0.04). The accuracy of sputum CFL1 in discriminating cancer patients from cancer-free patients and healthy volunteers were 0.78 and 0.69, respectively. CFL1 at a cut-off value of 415.25 pg/mL showed sensitivity/specificity of 0.80/0.70 in differentiating between healthy volunteers and cancer patients. Sputum CFL1 was also able to identify cancer-free patients from patients with lung cancer. The AUC was 0.70 and, at a cut-off point ≥662.63 pg/mL, we obtained 60% sensitivity and 54% specificity. Logistic regression analysis controlled for tobacco history, histologic types, and N stage showed that cancer cell-associated CFL1 was an independent predictor of death. Smoker patients with squamous cell carcinoma, lymph node metastasis and sputum CFL1>1.475 pg/mL showed augmented chance of death, suggesting lung cancer aggressiveness. CFL1 presented diagnostic value in detecting lung cancer and was associated to tumor aggressiveness.
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Escarro/química , Carcinoma de Células Escamosas/química , Biomarcadores Tumorais/análise , Cofilina 1/análise , Neoplasias Pulmonares/química , Prognóstico , Ensaio de Imunoadsorção Enzimática , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Curva ROC , Sensibilidade e Especificidade , Proliferação de Células , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Invasividade Neoplásica , Estadiamento de NeoplasiasRESUMO
Chaga's disease is an important communicable neglected disease that is gaining wider attention due to its increasing incidence worldwide. Achalasia due to chagasic megaesophagus (CM), a complication of this disease, is a known-yet, poorly understood-etiological factor for esophageal squamous cell carcinoma (ESCC) development. In this study, we aimed to perform the analysis of TP53 mutations in a series of Brazilian patients with ESCC that developed in the context CM (ESCC/CM), and to compare with the TP53 mutation profile of patients with benign CM and patients with nonchagasic ESCC. Additionally, we intended to correlate the TP53 mutation results with patient's clinical pathological features. By polymerase chain reaction (PCR) followed by direct sequencing of the hotspot regions of TP53 (exon 5 to 8), we found that TP53 mutations were present in 40.6% (13/32) of the ESCC/CM group, 45% (18/40) of the nonchagasic ESCC group, and in only 3% (1/33) of the benign CM group. Missense mutations were the most common in the three groups, yet, the type and mutated exon mutation varied significantly among the groups. Clinically, the groups exhibited distinct features, with both cancer groups (ESCC and ESCC/CM) been significantly associated higher consumption of alcohol and tobacco, older age, worse Karnofsky performance status, poor outcome than the patients with benign CM. No significant association was found between TP53 mutation profile and clinical-pathological features in any of the three groups. We describe first the time the analysis of TP53 mutations in ESCC that developed in the context of CM, and the observed high frequency of mutations, suggest that TP53 also plays an important role in the tumorigenic process of this unexplored etiological condition.
Assuntos
Carcinoma de Células Escamosas/genética , Doença de Chagas/genética , Acalasia Esofágica/genética , Neoplasias Esofágicas/genética , Genes p53 , Mutação , Adulto , Idoso , Brasil , Doença de Chagas/complicações , Acalasia Esofágica/complicações , Carcinoma de Células Escamosas do Esôfago , Éxons , Feminino , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Adulto JovemRESUMO
BRAF inhibitor (BRAFi) therapy for melanoma patients harboring the V600E mutation is initially highly effective, but almost all patients relapse within a few months. Understanding the molecular mechanisms underpinning BRAFi-based therapy is therefore an important issue. Here we identified a previously unsuspected mechanism of BRAFi resistance driven by elevated Hedgehog (Hh) pathway activation that is observed in a cohort of melanoma patients after vemurafenib treatment. Specifically, we demonstrate that melanoma cell lines, with acquired in vitro-induced vemurafenib resistance, show increased levels of glioma-associated oncogene homolog 1 and 2 (GLI1/GLI2) compared with naïve cells. We also observed these findings in clinical melanoma specimens. Moreover, the increased expression of the transcription factors GLI1/GLI2 was independent of canonical Hh signaling and was instead correlated with the noncanonical Hh pathway, involving TGFß/SMAD (transforming growth factor-ß/Sma- and Mad-related family) signaling. Knockdown of GLI1 and GLI2 restored sensitivity to vemurafenib-resistant cells, an effect associated with both growth arrest and senescence. Treatment of vemurafenib-resistant cells with the GLI1/GLI2 inhibitor Gant61 led to decreased invasion of the melanoma cells in a three-dimensional skin reconstruct model and was associated with a decrease in metalloproteinase (MMP2/MMP9) expression and microphthalmia transcription factor upregulation. Gant61 monotherapy did not alter the drug sensitivity of naïve cells, but could reverse the resistance of melanoma cells chronically treated with vemurafenib. We further noted that alternating dosing schedules of Gant61 and vemurafenib prevented the onset of BRAFi resistance, suggesting that this could be a potential therapeutic strategy for the prevention of therapeutic escape. Our results suggest that targeting the Hh pathway in BRAFi-resistant melanoma may represent a viable therapeutic strategy to restore vemurafenib sensitivity, reducing or even inhibiting the acquired chemoresistance in melanoma patients.
Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos , Indóis/farmacologia , Fatores de Transcrição Kruppel-Like/antagonistas & inibidores , Melanoma/metabolismo , Sulfonamidas/farmacologia , Proteína GLI1 em Dedos de Zinco/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Senescência Celular/genética , Expressão Gênica , Técnicas de Silenciamento de Genes , Proteínas Hedgehog/metabolismo , Humanos , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Melanoma/tratamento farmacológico , Melanoma/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Vemurafenib , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismo , Proteína Gli2 com Dedos de ZincoRESUMO
Cediranib, a pan-tyrosine kinase inhibitor is showing promising results for the treatment of several solid tumours. In breast cancer, its effects remain unclear, and there are no predictive biomarkers. Several studies have examined the expression profiles of microRNAs (miRNAs) in response to different chemotherapy treatments and found that the expression patterns may be associated with the treatment response. Therefore, our aim was to evaluate the cellular behaviour and differential expression profiles of miRNAs in breast cancer cell lines exposed to cediranib. The biological effect of this drug was measured by viability, migration, invasion and cell death in in vitro assays. Signaling pathways were assessed using a human phospho-receptor tyrosine kinase array. Furthermore, using a miRNA array and quantitative real-time PCR (qRTPCR), we assessed the relative expression of miRNAs following cediranib treatment. The breast cancer cell lines exhibited a distinct cytotoxic response to cediranib treatment. Cediranib exposure resulted in a decrease in the cell migration and invasion of all the breast cancer cell lines. Treatment with cediranib appeared to be able to modulate the activation of several RTKs that are targets of cediranib such as EGFR and a new potential target ROR2. Furthermore, this drug was able to modulate the expression profile of different microRNAs such as miR-494, miR-923, miR-449a, miR-449b and miR-886-3 in breast cancer cell lines. These miRNAs are reported to regulate genes involved in important molecular processes, according to bioinformatics prediction tools.
Assuntos
Antineoplásicos/farmacologia , MicroRNAs/genética , Quinazolinas/farmacologia , Transcriptoma/efeitos dos fármacos , Neoplasias da Mama , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Ontologia Genética , Humanos , Concentração Inibidora 50 , MicroRNAs/metabolismoRESUMO
Testicular germ cell tumors (TGCT) are the most common malignant neoplasm in young men. DNA mismatch repair deficiency can lead to microsatellite instability (MSI), an important mechanism of genetic instability. A mutation of the BRAF gene has been implicated in the pathogenesis of several solid tumors and has recently become an important therapeutic target. The role of MSI and BRAF gene mutation in TGCT, particularly in refractory disease, is poorly understood and reported findings are controversial. In this study, we aimed to determine the frequency and clinical impact of MSI status and BRAF mutations in TGCT. DNA was isolated from formalin-fixed paraffin embedded (FFPE) tissue from 150 TGCT cases. The MSI phenotype was evaluated using multiplex PCR for five quasimonomorphic mononucleotide repeat markers. Exon 15 of the BRAF oncogene (V600E) was analyzed by PCR, followed by direct sequencing. Sixteen percent of cases were considered to have refractory disease. In a small subset of cases (17 for MSI and 18 for BRAF), the quantity and quality of DNA recovery were poor and therefore, were unable to be analyzed. The remaining 133 TGCT cases showed a complete absence of MSI. Of the 132 cases successfully evaluated for BRAF mutations, all were V600E wild-type. In conclusion, despite a distinct response of testicular germ cell tumors to therapy, microsatellite instability, and the BRAF V600E mutation were absent in all testicular germ cell tumors tested in this study.
Assuntos
Instabilidade de Microssatélites , Mutação , Neoplasias Embrionárias de Células Germinativas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Testiculares/genética , Adolescente , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Neoplasias Embrionárias de Células Germinativas/patologia , Fenótipo , Proto-Oncogene Mas , Neoplasias Testiculares/patologia , Adulto JovemRESUMO
Este trabalho descreve o desenvolvimento de um método que classifica de forma semi-automática a degeneração de discos intervertebrais lombares em imagens de ressonância magnética ponderadas em T2. O conjunto de imagens consiste de 210 discos extraídos de exames de 94 indivíduos (20 a 80 anos). A classificação é feita por uma rede neural do tipo perceptron multicamada com 6 entradas, 15 neurônios na camada intermediária e 1 saída. Os resultados obtidos mostraram uma taxa média de acerto de 81,42%, com erro padrão de 9,11%.
This article describes the development of a method that classifies semi-automatic degeneration of lumbar intervertebral discs in magnetic resonance T2-weighted images. The dataset consists of images of 210 discs obtained from94 individuals (20 to 80 year old). An artificial neural network of the multilayer perceptron with 6 inputs, 15 neuronsin the hidden layer and 1 output, was used to check the efficiency of this study. Obtained an average rate of sucess of81.42%, with a standard error of 9.11%.
Assuntos
Humanos , Imageamento por Ressonância Magnética , Degeneração do Disco Intervertebral/classificação , Pesos e Medidas , Congressos como AssuntoRESUMO
Hyaluronan (HA) shows promise for detecting cancerous change in pleural effusion and urine. However, there is uncertainty about the localization of HA in tumor tissue and its relationship with different histological types and other components of the extracellular matrix, such as angiogenesis. We evaluated the association between HA and degree of malignancy through expression in lung tumor tissue and sputum. Tumoral tissue had significantly increased HA compared to normal tissue. Strong HA staining intensity associated with cancer cells was significant in squamous cell carcinoma compared to adenocarcinoma and large cell carcinoma. A significant direct association was found between tumors with a high percentage of HA and MVD (microvessel density) in tumoral stroma. Similarly significant was the direct association between N1 tumors and high levels of HA in cancer cells. Cox multivariate analysis showed significant association between better survival and low HA. HA increased in sputum from lung cancer patients compared to cancer-free and healthy volunteers and a significant correlation was found between HA in sputum and HA in cancer tissue. Localization of HA in tumor tissue was related to malignancy and reflected in sputum, making this an emerging factor for an important diagnostic procedure in patients suspected to have lung cancer. Further study in additional patients in a randomized prospective trial is required to finalize these results and to validate our quantitative assessment of HA, as well as to couple it to gold standard sputum cytology.
Assuntos
Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma/química , Ácido Hialurônico/análise , Neoplasias Pulmonares/química , Escarro/química , Biópsia , Biomarcadores Tumorais/análise , Estudos de Casos e Controles , Carcinoma/patologia , Ensaio de Imunoadsorção Enzimática , Imuno-Histoquímica , Neoplasias Pulmonares/patologia , Pulmão/química , Pulmão/patologia , Estadiamento de Neoplasias , Reprodutibilidade dos Testes , Fatores de Risco , Sensibilidade e Especificidade , Estatísticas não Paramétricas , Fumar/efeitos adversos , Células Estromais/química , Células Estromais/patologiaRESUMO
Hyaluronan (HA) shows promise for detecting cancerous change in pleural effusion and urine. However, there is uncertainty about the localization of HA in tumor tissue and its relationship with different histological types and other components of the extracellular matrix, such as angiogenesis. We evaluated the association between HA and degree of malignancy through expression in lung tumor tissue and sputum. Tumoral tissue had significantly increased HA compared to normal tissue. Strong HA staining intensity associated with cancer cells was significant in squamous cell carcinoma compared to adenocarcinoma and large cell carcinoma. A significant direct association was found between tumors with a high percentage of HA and MVD (microvessel density) in tumoral stroma. Similarly significant was the direct association between N1 tumors and high levels of HA in cancer cells. Cox multivariate analysis showed significant association between better survival and low HA. HA increased in sputum from lung cancer patients compared to cancer-free and healthy volunteers and a significant correlation was found between HA in sputum and HA in cancer tissue. Localization of HA in tumor tissue was related to malignancy and reflected in sputum, making this an emerging factor for an important diagnostic procedure in patients suspected to have lung cancer. Further study in additional patients in a randomized prospective trial is required to finalize these results and to validate our quantitative assessment of HA, as well as to couple it to gold standard sputum cytology.
Assuntos
Carcinoma/química , Ácido Hialurônico/análise , Neoplasias Pulmonares/química , Escarro/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Biópsia , Carcinoma/patologia , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imuno-Histoquímica , Pulmão/química , Pulmão/patologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Reprodutibilidade dos Testes , Fatores de Risco , Sensibilidade e Especificidade , Fumar/efeitos adversos , Estatísticas não Paramétricas , Células Estromais/química , Células Estromais/patologiaRESUMO
Colorectal cancer (CRC) is one of the most frequent cancers worldwide. Adenoma is the main precursor lesion and, recently, the serrated polyps were described as a group of colorectal lesions with malignant potential. The morphologic and biologic characterizations of serrated polyps remain limited. The aim of the present study was to determine the frequency of KRAS and BRAF mutations and microsatellite instability (MSI) in CRC precursor lesions, to evaluate the association between molecular, pathologic and morphologic alterations in precursor lesions and to compare with the alterations detected in CRC. A series of 342 precursor lesions were removed from 155 patients during colonoscopy. After morphologic classification, molecular analysis was performed in 103 precursor lesions, and their genetic profile compared with 47 sporadic CRCs. Adenomas were the main precursor lesions (70.2%). Among the serrated polyps, the main precursor lesion was hyperplastic polyps (HPs) (82.4%), followed by sessile serrated adenomas (12.7%) and traditional serrated adenomas (2.0%). KRAS mutations were detected in 13.6% of the precursor lesions, namely in adenomas and in HPs, but in no serrated adenoma. BRAF mutations were found in 9 (8.7%) precursor lesions, mainly associated with serrated polyps and absent in adenomas (P<0.001). High MSI (MSI-H) was absent in precursor lesions. In the 47 CCR cases, 46.8% exhibited KRAS mutation, 6.5% BRAF mutations and 10.6% MSI-H. This study confirms the role of KRAS and BRAF mutations in CRC carcinogenesis, a crucial step in implementing CRC screening strategies.
Assuntos
Adenocarcinoma/genética , Adenoma/genética , Pólipos do Colo/genética , Neoplasias Colorretais/genética , Instabilidade de Microssatélites , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas/genética , Proteínas ras/genética , Adenocarcinoma/patologia , Adenoma/patologia , Idoso , Idoso de 80 Anos ou mais , Pólipos do Colo/patologia , Colonoscopia , Neoplasias Colorretais/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Proto-Oncogênicas p21(ras)RESUMO
PURPOSE: To correlate ovarian reserve (OR) markers with response in assisted reproduction techniques (ART) and determine their ability to predict poor response among patients with endometriosis (EDT). METHODS: We evaluated ART cycles of 27 women with EDT and 50 with exclusive male factor. Basal follicle stimulating hormone (FSH) and anti-müllerian hormone (AMH) levels were determined. Ovarian response to gonadotropin stimulation was assessed and correlation coefficients calculated between the variables and reserve markers. Areas under the curve (AUC) determined ability of tests to predict poor response. RESULTS: AMH was significantly correlated with response in both groups and it was the only marker with significant discriminative capacity to predict poor response among EDT (AUC = 0.842; 95% CI: 0.651-0.952) and control group (AUC = 0.869; 95% CI: 0.743-0.947). CONCLUSION: Infertile patients with endometriosis can benefit from the pre-therapeutic assessment of OR markers. However, regardless of disease presence, only AMH predicts poor response to stimulus.
Assuntos
Hormônio Antimülleriano/sangue , Endometriose/sangue , Hormônio Foliculoestimulante/sangue , Ovário/fisiologia , Indução da Ovulação/métodos , Injeções de Esperma Intracitoplásmicas/métodos , Endometriose/complicações , Endometriose/terapia , Feminino , Humanos , Infertilidade Feminina/etiologia , Infertilidade Masculina , Masculino , Curva ROCRESUMO
BACKGROUND: There is evidence that intrauterine growth restriction, resulting in newborn girls that are small for gestational age (SGA), may be related to the onset of polycystic ovary syndrome (PCOS). Thus, we studied whether women born SGA have a higher prevalence of PCOS than women born appropriate for gestational age (AGA). METHODS: This was a prospective birth cohort study of 384 women born at term between June 1, 1978, and May 31, 1979, in Ribeirão Preto, Brazil. After exclusion, 165 women effectively participated in this study, of whom 43 were SGA and 122 were AGA. The prevalence of PCOS was analysed. At a mean age of 29 years, the women agreed to follow the study protocol, which included: anamnesis, physical examination, serum tests [follicle stimulating hormone, luteinizing hormone, total and free testosterone, dehydroepiandrostenedione sulphate, 17-OH-progesterone, fasting insulin, sex steroid-binding globulin (SHBG) and fasting glucose] and pelvic ultrasound. Data regarding gestational age, birthweight, age at menarche and maternal data were obtained from the files of the cohort. The adjusted relative risk (RR) values of the SGA, insulin resistance, body mass index, maternal smoking and parity variables were analysed using Poisson regression with robust adjustment of variance for the prediction of PCOS. RESULTS: The prevalence of PCOS was higher in the SGA group than in the AGA group [adjusted RR = 2.44, 95% CI (1.39-4.28)]. Hyperandrogenism was more prevalent in the SGA women than in the AGA women (P = 0.011). Circulating SHBG was lower in the SGA women than in the AGA women (P = 0.041), but fasting insulinemia was similar in both groups. CONCLUSIONS: The prevalence of PCOS in SGA women was twice as high as in AGA women in our study population.
Assuntos
Peso ao Nascer , Síndrome do Ovário Policístico/epidemiologia , Adulto , Feminino , Idade Gestacional , Humanos , Distribuição de Poisson , Síndrome do Ovário Policístico/sangue , Prevalência , Estudos Prospectivos , Análise de Regressão , Fatores de RiscoRESUMO
PURPOSE OF INVESTIGATION: Celiac disease (CD) involves immunologically mediated intestinal damage with consequent micronutrient malabsorption and varied clinical manifestations, and there is a controversial association with infertility. The objective of the present study was to determine the presence of CD in a population of infertile women with endometriosis. METHODS: A total of 120 women with a diagnosis of endometriosis confirmed by laparoscopy (study group) and 1,500 healthy female donors aged 18 to 45 years were tested for CD by the determination of IgA-transglutaminase antibody against human tissue transglutaminase (t-TGA) and anti-endomysium (anti-EMA) antibodies. RESULTS: Nine of the 120 women in the study group were anti-tTGA positive and five of them were also anti-EMA positive. Four of these five patients were submitted to intestinal biopsy which revealed CD in three cases (2.5% prevalence). The overall CD prevalence among the population control group was 1:136 women (0.66%). CONCLUSION: This is the first study reporting the prevalence of CD among women with endometriosis, showing that CD is common in this population group (2.5%) and may be clinically relevant.
Assuntos
Doença Celíaca/diagnóstico , Endometriose/complicações , Infertilidade Feminina/complicações , Adolescente , Adulto , Autoanticorpos/sangue , Brasil/epidemiologia , Estudos de Casos e Controles , Doença Celíaca/complicações , Doença Celíaca/epidemiologia , Feminino , Humanos , Imunoglobulina A/imunologia , Pessoa de Meia-Idade , Projetos Piloto , Prevalência , Testes Sorológicos , Transglutaminases/imunologia , Adulto JovemRESUMO
Chronic anovulation, polycystic ovarian morphology and hyperandrogenism are the diagnostic criteria for polycystic ovary syndrome (PCOS). Metabolic disturbances are more common in PCOS women who are prone to develop metabolic syndrome and to present higher levels of some cardiovascular disease risk marker. Oral contraceptives are widely used in PCOS, but conflicting data have been reported regarding their impact on carbohydrate and lipid metabolism on PCOS women. This paper presents a critical evaluation of combined oral contraceptives (COCs) metabolic effect - carbohydrate metabolism and insulin sensitivity, lipid metabolism, haemostasis, body weight, arterial pressure and cardiovascular impact - on PCOS women. Because of the paucity of data on the impact of COCs on cardiovascular and metabolic parameters in PCOS patients, most of there commendations are based on studies involving ovulatory women. The use of low-dose COCs is preferable in PCOS, especially among patients with glucose intolerance, insulin resistance and uncomplicated diabetes mellitus. Although reported as a side effect of COCs, marked weight gain has not been confirmed among users. However, when arterial hypertension or elevated risk for thromboembolism is present, progestogen-only hormonal contraceptives should be used instead of COCs. Regarding dyslipidaemia, COCs reduce low-density lipoprotein and total cholesterol and elevate high-density lipoprotein and triglycerides, and therefore are not recommended for women with high triglycerides levels. The choice of a COC, which alleviates the PCOS-induced hyperandrogenism without significant negative impact on cardiovascular risk, is one of the greatest challenges faced by gynaecologists nowadays.
Assuntos
Anticoncepcionais Orais Combinados/uso terapêutico , Doenças Metabólicas/induzido quimicamente , Síndrome do Ovário Policístico/tratamento farmacológico , Adulto , Anticoncepcionais Orais Combinados/efeitos adversos , Métodos Epidemiológicos , Feminino , Humanos , Pessoa de Meia-Idade , Aumento de Peso/efeitos dos fármacosRESUMO
OBJECTIVE: To determine the validity and the intra- and interobserver reliability of volume measurements of an endometrium-like model using a three-dimensional (3D) ultrasound rotational technique. METHODS: A 3D ultrasound dataset was obtained from a sample of bovine liver containing a portion of chicken chest muscle (CCM). The process was repeated seven times using pieces of CCM of different sizes, resulting in seven datasets. Each portion of CCM was then placed in a water-filled volume-scaled tube and the 'actual' volumes were calculated by water displacement. For each dataset, ten volumes were calculated by each of two observers using a (VOCAL) with a 15 degrees rotational step. Reliability was assessed by calculating intraclass correlation coefficients (ICC) and validity by examining the percentage difference from the actual volume using limits of agreement. RESULTS: The volume measurement of organic tissues using the 3D ultrasound rotational method was highly reliable (intraobserver ICC, 0.998 for Observer 1 and 0.997 for Observer 2; interobserver ICC, 0.997) and valid (the bias and 95% limits of agreement of the percentage difference from the actual volume was only 0.57 (-3.07 to 4.21) % for Observer 1 and - 0.17 (-4.34 to 4.0) % for Observer 2). CONCLUSIONS: The 3D sonographic measurement, using VOCAL with a 15 degrees rotational step, of small and irregular tissues is reliable and valid, suggesting that it is a useful technique for measurement of the endometrial volume and other volumes of similar size.
Assuntos
Endométrio/diagnóstico por imagem , Imageamento Tridimensional/normas , Ultrassonografia Pré-Natal/normas , Animais , Aves , Bovinos , Galinhas , Feminino , Imageamento Tridimensional/instrumentação , Imageamento Tridimensional/métodos , Fígado , Modelos Biológicos , Músculo Esquelético , Gravidez , Reprodutibilidade dos Testes , Ultrassonografia Pré-Natal/instrumentação , Ultrassonografia Pré-Natal/métodosRESUMO
BACKGROUND: The present study assessed the effects of low-dose acarbose on obese patients with polycystic ovarian syndrome (PCOS). METHODS: A double-blind placebo-controlled study was conducted on 30 obese hyperinsulinaemic women with PCOS treated with 150 mg/day acarbose or placebo for 6 months. The women were evaluated for hirsutism, menstrual regularity, body mass index (BMI), insulin resistance and glucose tolerance, sex hormone-binding globulin (SHBG), LH, FSH, testosterone and androstenedione, and side-effects. RESULTS: The patients in the acarbose group showed a reduction in BMI (35.87 +/- 2.60 versus 33.10 +/- 2.94 kg/m(2)) and in the Ferriman-Gallwey index (8.85 +/- 2.31 versus 8 +/- 1.82), and an increased chance of menstrual regularity (rate = 2.67). SHBG concentration increased (21.01 +/- 7.9 versus 23.85 +/- 7.77 nmol/l) and the free androgen index was reduced (14.81 +/- 9.06 versus 11.48 +/- 6.18). None of these parameters were modified in the placebo group. Mild side-effects occurred in 84% of the patients in the acarbose group and disappeared after the first 3 months. CONCLUSION: A low dose of acarbose administered to obese patients with PCOS promotes a reduction in free androgen index and BMI and an increase in SHBG, with improvement of hirsutism and of the menstrual pattern, and is well tolerated by patients.
Assuntos
Acarbose/administração & dosagem , Hipoglicemiantes/administração & dosagem , Obesidade/tratamento farmacológico , Síndrome do Ovário Policístico/tratamento farmacológico , Administração Oral , Adulto , Peso Corporal/efeitos dos fármacos , Método Duplo-Cego , Feminino , Humanos , Hiperandrogenismo/tratamento farmacológico , Hiperandrogenismo/etiologia , Hiperinsulinismo/tratamento farmacológico , Hiperinsulinismo/etiologia , Obesidade/etiologia , Placebos , Síndrome do Ovário Policístico/complicações , Estudos ProspectivosRESUMO
A longitudinal prospective study was conducted in 21 women with polycistic ovary syndrome (PCOS), aged 27.20 +/- 5.02 years and treated with metformin (1500 mg/day)for 8 weeks. The patients were assessed for spontaneous menstruation, weight, body mass index (BMI), waist circumference, waist/hip ratio (WHR), glucose and insulin concentrations under fasting conditions and after a 75-g glucose tolerance test, lipid profile, testosterone, androstenedione, dehydroepiandrosterone sulfate, sex-hormone binding globulin (SHBG), and insulin-like growth factor (IGF)-I. Spontaneous menstruation was observed in 81% of the women treated with metformin, with no changes in weight or BMI. Waist measurement and the WHR were reduced. The quantitative insulin sensitivity check index (QUICKI) improved from 0.33 +/- 0.03 to 0.35 +/- 0.04 (p < 0.005), and serum total cholesterol and low-density lipoprotein-cholesterol were reduced, while high-density lipoprotein-cholesterol was increased. Serum testosterone concentrations were also reduced. There were no differences in serum triglycerides, SHBG or IGF-I. The occurrence of spontaneous menstruation and changes in the pattern of body fat distribution, the reduction in serum testosterone concentrations, the improvement in lipid profile and the reduction of insulinemia with the use of metformin permit us to conclude that treatment with this drug is of benefit to women with PCOS.