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1.
Cell Oncol (Dordr) ; 43(5): 915-929, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32761561

RESUMO

PURPOSE: Although doxorubicin is widely used to treat cancer, severe side effects limit its clinical use. Combination of standard chemotherapy with natural products can increase the efficacy and attenuate the side effects of current therapies. Here we studied the anticancer effects of a combined regimen comprising doxorubicin and [10]-gingerol against triple-negative breast cancer, which does not respond to hormonal or targeted therapies. METHODS: Cytotoxicity was evaluated by MTT assay, cell cycle progression and apoptosis were analyzed by flow cytometry and signaling pathways were analyzed by Western blotting in human and murine triple negative breast cancer cell systems. The anticancer/antimetastatic and toxic effects of the combined regimen was evaluated using syngeneic and xenograft orthotopic models. RESULTS: The combination of doxorubicin and [10]-gingerol significantly increased the number of apoptotic cells, compared to each compound alone. In 4T1Br4 cells, the combined regimen was the only condition able to increase the levels of active caspase 3 and γH2AX and to decrease the level of Cdk-6 cyclin. In vivo, doxorubicin (3 mg/Kg, D3) and [10]-gingerol (10 mg/Kg, G10) resulted in a significant reduction in the volume of primary tumors and a decrease in the number of circulating tumor cells (CTCs). Interestingly, only the combined regimen led to decreased tumor burdens to distant organs (i.e., metastasis) and reduced chemotherapy-induced weight loss and hepatotoxicity in tumor-bearing animals. Likewise, in a xenograft model, only the combined regimen was effective in significantly reducing the primary tumor volume and the prevalence of CTCs. CONCLUSIONS: Our data indicate that [10]-gingerol has potential to be used as a neoadjuvant or in combined therapy with doxorubicin, to improve its anticancer activity.

2.
BMC Cancer ; 20(1): 143, 2020 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-32087690

RESUMO

BACKGROUND: MicroRNAs (miRNAs) are small non-coding RNAs involved in post-transcriptional gene expression regulation and have been described as key regulators of carcinogenesis. Aberrant miRNA expression has been frequently reported in sporadic breast cancers, but few studies have focused on profiling hereditary breast cancers. In this study, we aimed to identify specific miRNA signatures in hereditary breast tumors and to compare with sporadic breast cancer and normal breast tissues. METHODS: Global miRNA expression profiling using NanoString technology was performed on 43 hereditary breast tumors (15 BRCA1, 14 BRCA2, and 14 BRCAX), 23 sporadic breast tumors and 8 normal breast tissues. These normal breast tissues derived from BRCA1- and BRCA2- mutation carriers (n = 5) and non-mutation carriers (n = 3). Subsequently, we performed receiver operating characteristic (ROC) curve analyses to evaluate the diagnostic performance of differentially expressed miRNAs. Putative target genes of each miRNAs considered as potential biomarkers were identified using miRDIP platform and used for pathway enrichment analysis. RESULTS: miRNA expression analyses identified several profiles that were specific to hereditary breast cancers. A total of 25 miRNAs were found to be differentially expressed (fold change: > 2.0 and p < 0.05) and considered as potential biomarkers (area under the curve > 0.75) in hereditary breast tumors compared to normal breast tissues, with an expressive upregulation among BRCAX cases. Furthermore, bioinformatic analysis revealed that these miRNAs shared target genes involved in ErbB, FoxO, and PI3K-Akt signaling pathways. CONCLUSIONS: Our results showed that miRNA expression profiling can differentiate hereditary from sporadic breast tumors and normal breast tissues. These miRNAs were remarkably deregulated in BRCAX hereditary breast cancers. Therefore, miRNA signatures can be used as potential novel diagnostic biomarkers for the prediction of BRCA1/2- germline mutations and may be useful for future clinical management.


Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Regulação Neoplásica da Expressão Gênica , Mutação em Linhagem Germinativa , MicroRNAs/genética , Adulto , Idoso , Brasil , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Pessoa de Meia-Idade , Curva ROC
3.
Cells ; 9(2)2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-32093151

RESUMO

Autophagy is a cell-survival pathway with dual role in tumorigenesis, promoting either tumor survival or tumor death. WNK2 gene, a member of the WNK (with no lysine (K)) subfamily, acts as a tumor suppressor gene in gliomas, regulating cell migration and invasion; however, its role in autophagy process is poorly explored. The WNK2-methylated human glioblastoma cell line A172 WT (wild type) was compared to transfected clones A172 EV (empty vector), and A172 WNK2 (WNK2 overexpression) for the evaluation of autophagy using an inhibitor (bafilomycin A1-baf A1) and an inducer (everolimus) of autophagic flux. Western blot and immunofluorescence approaches were used to monitor autophagic markers, LC3A/B and SQSTM1/p62. A172 WNK2 cells presented a significant decrease in LC3B and p62 protein levels, and in LC3A/B ratio when compared with control cells, after treatment with baf A1 + everolimus, suggesting that WNK2 overexpression inhibits the autophagic flux in gliomas. The mTOR pathway was also evaluated under the same conditions, and the observed results suggest that the inhibition of autophagy mediated by WNK2 occurs through a mTOR-independent pathway. In conclusion, the evaluation of the autophagic process demonstrated that WNK2 inhibits the autophagic flux in glioblastoma cell line.

4.
PLoS One ; 14(10): e0220086, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31600211

RESUMO

BACKGROUND: Endometrial cancer presents well-defined risk factors: myometrial invasion, histological subtype, tumor grade, lymphovascular space invasion (LVSI). Some low and intermediate-risk endometrioid endometrial cancer patients exhibited unexpected outcomes. This study aimed to investigate other clinical-pathological factors that might influence the recurrence rates of patients diagnosed with low and intermediate-risk endometrioid endometrial cancer. METHODS: A case-control study from a cohort retrospective of 196 patients diagnosed with low and intermediate-risk endometrioid endometrial cancer at a single institution from 2009 to 2014 was conducted. Medical records were reviewed to compare clinical (race, smoking, menopause age, body mass index) and pathological (endometrioid vs endometrioid with squamous differentiation, tumor differentiation grade, tumor location, endocervical invasion, LVSI) features of patients with recurrence (case) and without recurrence (control) of disease. Three controls for each case were matched for age and staging. RESULTS: Twenty-one patients with recurrence were found (10.7%), of which 14 were stage IA, and 7 were stage IB. In accordance, 63 patients without recurrence were selected as controls. There were no significant differences in any clinical characteristics between cases and controls. Among pathological variables, presence of squamous differentiation (28.6% vs. 4.8%, p = 0.007), tumor differentiation grade 2 or 3 (57.1% vs. 30.2%, p = 0.037) and presence of endocervical invasion (28.6% vs. 12.7%, p = 0.103) were associated with disease recurrence on a univariate analysis. On multivariable analysis, only squamous differentiation was a significant risk factor for recurrence (p = 0.031). CONCLUSION: Our data suggest that squamous differentiation may be an adverse prognostic factor in patients with low and intermediate-risk endometrioid endometrial cancer, that showed a 5.6-fold increased risk for recurrence.


Assuntos
Carcinoma Endometrioide , Neoplasias do Endométrio , Idoso , Carcinoma Endometrioide/diagnóstico , Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/patologia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Estudos Retrospectivos , Fatores de Risco
5.
PLoS One ; 14(6): e0217585, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31220088

RESUMO

BACKGROUND: Renal fibrosis is the result of the interaction of cellular and molecular pathways, which is induced by sustained glomerular injury and involves the podocytes and multiple profibrotic factors. In this study, we investigated the correlation of the mRNA expression of podocyte proteins and profibrotic factors with renal fibrosis measured in renal biopsies of patients with primary and secondary glomerulopathies. METHODS: Eighty-four adult patients with primary or secondary glomerular diseases and 12 controls were included. Demographic and clinical data were collected. Seventy-two percent of the renal biopsies were done less than one year from clinical disease manifestation. The quantification of the podocyte-associated mRNAs of alpha-actinin-4, podocin, and podocalyxin, as well as of the profibrotic factors TGF-ß1, CTGF, and VEGF-A were quantified by real-time polymerase chain reaction. The percent positive area of renal fibrosis was measured by immunohistochemistry staining, using anti-CTGF and anti-HHF35 antibodies and unpolarized Sirius Red. Correlations between the expression of tissue mRNAs and the positive area of fibrosis for the measured markers were made by Spearman's rank correlation coefficient. RESULTS: In relation to control biopsies, podocyte-specific proteins were downregulated in podocytopathies, in proliferative nephritis, in diabetic kidney disease (DRD), and in IgA nephropathy (IgAN). Messenger RNA of TGF-ß1, CTGF, and VEGF-A was upregulated in patients with podocytopathies and in DRD but not in proliferative nephritis and IgAN. Tissue mRNA expression of TGF-ß1, CTGF, and VEGF-A were strongly correlated with renal fibrosis, as measured by HHF35; however, the correlation, albeit significant, was moderate for Sirius Red and weak for CTGF. The percent positive area of renal fibrosis measured by Sirius Red was similar between podocytopathies and DRD and significantly higher in podocytopathies compared to IgAN or proliferative nephritis. CONCLUSIONS: In patients with glomerular diseases, the mRNA of TGF-ß1, CTGF, and VEGF-A correlated positively with the extent of renal fibrosis, and the positive area of fibrosis was larger in the podocytopathies and in DRD as measured by Sirius Red. The pathways connecting podocyte damage and activation of profibrotic factors to kidney tissue fibrosis need to be better investigated.


Assuntos
Glomérulos Renais/patologia , Podócitos/patologia , Adulto , Biomarcadores/metabolismo , Biópsia , Fator de Crescimento do Tecido Conjuntivo/genética , Feminino , Humanos , Glomérulos Renais/metabolismo , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , Fator de Crescimento Transformador beta1/genética , Fator A de Crescimento do Endotélio Vascular/genética
6.
BMC Cancer ; 19(1): 5, 2019 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-30606144

RESUMO

BACKGROUND: The present study aims to assess the performance of 18F-FDG PET-CT on mediastinal staging of non-small cell lung cancer (NSCLC) in a location with endemic granulomatous infectious disease. METHODS: Diagnostic test study including patients aged 18 years or older with operable stage I-III NSCLC and indication for a mediastinal lymph node biopsy. All patients underwent a 18F-FDG PET-scan before invasive mediastinal staging, either through mediastinoscopy or thoracotomy, which was considered the gold-standard. Surgeons and pathologists were blinded for scan results. Primary endpoint was to evaluate sensitivity, specificity and positive and negative predictive values of PET-CT with images acquired in the 1st hour of the exam protocol, using predefined cutoffs of maximal SUV, on per-patient basis. RESULTS: Overall, 85 patients with operable NSCLC underwent PET-CT scan followed by invasive mediastinal staging. Mean age was 65 years, 49 patients were male and 68 were white. One patient presented with active tuberculosis and none had HIV infection. Using any SUV_max > 0 as qualitative criteria for positivity, sensitivity and specificity were 0.87 and 0.45, respectively. Nevertheless, even when the highest SUV cut-off was used (SUV_max ≥5), specificity remained low (0.79), with an estimated positive predictive value of 54%. CONCLUSIONS: Our findings are in line with the most recent publications and guidelines, which recommend that PET-CT must not be solely used as a tool to mediastinal staging, even in a region with high burden of tuberculosis. TRIAL REGISTRATION: The LACOG 0114 study was registered at ClinicalTrials.gov , before study initiation, under identifier NCT02664792.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Estadiamento de Neoplasias/métodos , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Tuberculose/diagnóstico por imagem , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/patologia , Testes Diagnósticos de Rotina/métodos , Doenças Endêmicas , Feminino , Humanos , Masculino , Mediastinoscopia , Mediastino/diagnóstico por imagem , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X , Tuberculose/complicações , Tuberculose/diagnóstico , Tuberculose/patologia
7.
Am J Clin Dermatol ; 20(2): 277-287, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30618025

RESUMO

BACKGROUND: Striae distensae (SD), an unsightly cutaneous condition characterized by epidermal atrophy, can affect the quality of life of women. OBJECTIVES: The aim of our study was to compare the efficacy of a neodymium:yttrium-aluminum-perovskite 1340 nm non-ablative fractional laser (NAFL) and the microneedling (MN) technique to treat striae alba (SA). MATERIALS AND METHODS: NAFL and MN were used to treat striae on the longitudinally divided abdominal surface of 20 women classified as Fitzpatrick skin type III or IV (five sessions at monthly intervals). Photographs and skin biopsies were obtained during pretreatment and after the third and fifth treatment sessions for all patients. Patients and two independent evaluators assessed the clinical response using the Global Aesthetic Improvement Scale. RESULTS: Patient-reported evaluation showed improvement of striae using both modalities, with no statistically significant difference between the groups. Collagen and elastic fibers were significantly increased (p < 0.01) after the third and fifth treatment sessions, with no significant difference between the modalities. In addition, Dermatology Life Quality Index scores showed significant improvement (p < 0.001) after the third and fifth treatment sessions compared with pretreatment values, with average values of 8.4 (standard error [SE] ± 1.21), 3.17 (SE ± 0.55), and 2.64 (SE ± 0.60), respectively. The mean pain score using the Visual Analog Scale in the MN group versus the NAFL group was 5.23 (SE ± 0.31) versus 2.39 (SE ± 0.22) [p < 0.001], and the mean duration of adverse events in the NAFL group versus the MN group was 4.03 days (SE ± 0.45) versus 3 days (SE ± 0.37) [p = 0.02]. CONCLUSION: NAFL and MN are safe for treating SD, particularly in individuals classified as phototype III or IV. MN is a useful non-technology-dependent, low-cost alternative therapy for SA. CLINICAL TRIAL REGISTRATION NUMBER: NCT03390439.


Assuntos
Técnicas Cosméticas , Lasers de Estado Sólido/uso terapêutico , Agulhas , Estrias de Distensão/terapia , Adulto , Biópsia , Colágeno/metabolismo , Feminino , Humanos , Qualidade de Vida , Estrias de Distensão/patologia , Resultado do Tratamento
8.
Inflammation ; 41(5): 1987-2001, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29995294

RESUMO

Pulmonary fibrosis is a specific form of interstitial pneumonia. In addition to the idiopathic cause, it may be caused by drugs such as bleomycin (BLM)-used in the treatment of tumors. Fructose-1,6-bisphosphate (FBP) is a high-energy endogenous glycolytic compound that has antifibrotic, anti-inflammatory, and immunomodulatory effects. The aim of this study was to investigate the effects of FBP on both BLM-induced pulmonary fibrosis in mice and in a human embryonic lung fibroblast (MRC-5) culture system. C57BL/6 mice were divided into four groups: control, FBP, BLM, and BLM plus FBP. A single dose of bleomycin (7.5 U/kg) was administered intratracheally, and survival, body weight, Ashcroft score, and histological analysis were evaluated. Pulmonary function and bronchoalveolar lavage fluid (BALF) were also evaluated after a single dose of bleomycin (1.2 U/kg-intratracheally). Treatment with FBP (500 mg/kg) was given on day 0 intraperitoneally. Fibroblasts (MRC-5 cells) were used to access the effect of FBP in vitro. In vivo, FBP increased the survival rate and reduced body weight loss (BLM vs. BLM plus FBP-p < 0.05). FBP also prevented BLM-induced loss of pulmonary function and decreased BALF inflammatory cells, level of fibrosis, and superficial collagen density (p < 0.05). In vitro, FBP (0.62 and 1.25 mM) had inhibitory activity on MRC-5 cells and was able to induce senescence in fibroblasts. These results showed that FBP has the potential of reducing the toxic effects of BLM and may provide supportive therapy for conventional methods used for the treatment of cancer.


Assuntos
Fibroblastos/patologia , Frutosedifosfatos/farmacologia , Fibrose Pulmonar/prevenção & controle , Animais , Bleomicina/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Frutosedifosfatos/uso terapêutico , Humanos , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Fibrose Pulmonar/induzido quimicamente , Taxa de Sobrevida , Perda de Peso/efeitos dos fármacos
9.
World J Gastroenterol ; 23(25): 4529-4537, 2017 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-28740341

RESUMO

AIM: To evaluate the protective effects of glutamine in a model of portal hypertension (PH) induced by partial portal vein ligation (PPVL). METHODS: Male Wistar rats were housed in a controlled environment and were allowed access to food and water ad libitum. Twenty-four male Wistar rats were divided into four experimental groups: (1) control group (SO) - rats underwent exploratory laparotomy; (2) control + glutamine group (SO + G) - rats were subjected to laparotomy and were treated intraperitoneally with glutamine; (3) portal hypertension group (PPVL) - rats were subjected to PPVL; and (4) PPVL + glutamine group (PPVL + G) - rats were treated intraperitoneally with glutamine for seven days. Local injuries were determined by evaluating intestinal segments for oxidative stress using lipid peroxidation and the activities of glutathione peroxidase (GPx), endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS) after PPVL. RESULTS: Lipid peroxidation of the membrane was increased in the animals subjected to PH (P < 0.01). However, the group that received glutamine for seven days after the PPVL procedure showed levels of lipid peroxidation similar to those of the control groups (P > 0.05). The activity of the antioxidant enzyme GTx was decreased in the gut of animals subjected to PH compared with that in the control group of animals not subjected to PH (P < 0.01). However, the group that received glutamine for seven days after the PPVL showed similar GTx activity to both the control groups not subjected to PH (P > 0.05). At least 10 random, non-overlapping images of each histological slide with 200 × magnification (44 pixel = 1 µm) were captured. The sum means of all areas, of each group were calculated. The mean areas of eNOS staining for both of the control groups were similar. The PPVL group showed the largest area of staining for eNOS. The PPVL + G group had the second highest amount of staining, but the mean value was much lower than that of the PPVL group (P < 0.01). For iNOS, the control (SO) and control + G (SO + G) groups showed similar areas of staining. The PPVL group contained the largest area of iNOS staining, followed by the PPVL + G group; however, this area was significantly smaller than that of the group that underwent PH without glutamine (P < 0.01). CONCLUSION: Treatment with glutamine prevents gut mucosal injury after PH in rats.


Assuntos
Antioxidantes/farmacologia , Hipertensão Portal/tratamento farmacológico , Mucosa Intestinal/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/uso terapêutico , Modelos Animais de Doenças , Glutamina/farmacologia , Glutamina/uso terapêutico , Glutationa Peroxidase/metabolismo , Hipertensão Portal/patologia , Imuno-Histoquímica , Mucosa Intestinal/enzimologia , Mucosa Intestinal/patologia , Ligadura , Fígado/irrigação sanguínea , Masculino , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Veia Porta/patologia , Veia Porta/cirurgia , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico
10.
Rev Col Bras Cir ; 44(2): 131-139, 2017.
Artigo em Inglês, Português | MEDLINE | ID: mdl-28658331

RESUMO

Objective: to study the association between the histological grading of cervical intraepithelial neoplasia (CIN I, CIN II and CIN III) and the immunohistochemical expression for p16ink4a, hTert and Ki67, as well as to evaluate the relationship of these markers with the risk of recurrence after surgical treatment. Methods: we studied a historical cohort of 94 women with intraepithelial lesions CIN I (low grade), CIN II and CIN III (high grades) submitted to conization or electrosurgical excision of the transformation zone. We evaluated all surgical specimens for immunohistochemical expression of p16ink4a, hTert and Ki67. Results: the mean age was 38.2 years; p16ink4a was absent in most CIN I cases. In patients with CIN II or I/II (association of low and high-grade lesions), we observed p16ink4a ≤10%. In patients with CIN III, we found a higher expression frequency of p16ink4a >50%. In CIN I, the majority had Ki67≤10% and low frequency of Ki67>50%. In the CIN III category, there were fewer patients with Ki67≤10%, and Ki67 was absent in most patients of CIN II and III groups. There was no association between hTert expression and histologic grade. There were no statistically significant differences between the expression of the markers in patients with and without recurrence. Conclusion: there was a statistically significant association of p16ink4a and Ki67 with histological grade. The markers' expression, as for disease recurrence, was not statistically significant in the period evaluated.


Assuntos
Neoplasia Intraepitelial Cervical/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/biossíntese , Antígeno Ki-67/biossíntese , Telomerase/biossíntese , Adulto , Neoplasia Intraepitelial Cervical/patologia , Feminino , Humanos , Gradação de Tumores
11.
Exp Parasitol ; 177: 28-34, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28431921

RESUMO

A diagnostic test that is reliable, sensitive, and applicable in the field is extremely important in epidemiological surveys, during medical treatment for schistosomiasis, and for the control and elimination of schistosomiasis. The Helmintex (HTX) method is based on the use of magnetic beads to trap eggs in a magnetic field. This technique is highly sensitive, but the screening of fecal samples consumes lots of time, thus delaying the results, especially in field studies. The objective of this work was to determine the effects of incorporation of the detergent Tween-20 into the method in an attempt to decrease the final pellet volume produced by the HTX method as well as the use of ninhydrin to stain the Schistosoma mansoni eggs. We showed that these modifications reduced the final volume of the fecal sediment produced in the last step of the HTX method by up to 69% and decreased the screening time to an average of 10.1 min per sample. The use of Tween 20 and ninhydrin led to a high percentage of egg recovery (27.2%). The data obtained herein demonstrate that the addition of detergent and the use of ninhydrin to the HTX process can optimize the screening step and also improve egg recovery, thus justifying the insertion of these steps into the HTX method.


Assuntos
Fezes/parasitologia , Schistosoma mansoni/isolamento & purificação , Esquistossomose mansoni/diagnóstico , Animais , Celulase/metabolismo , Humanos , Indicadores e Reagentes , Campos Magnéticos , Camundongos , Ninidrina , Óvulo , Contagem de Ovos de Parasitas/métodos , Polissorbatos , Tensoativos , Fatores de Tempo , Fixação de Tecidos/métodos
12.
Rev. Col. Bras. Cir ; 44(2): 131-139, Mar.-Apr. 2017. tab, graf
Artigo em Inglês | LILACS | ID: biblio-842657

RESUMO

ABSTRACT Objective : to study the association between the histological grading of cervical intraepithelial neoplasia (CIN I, CIN II and CIN III) and the immunohistochemical expression for p16ink4a, hTert and Ki67, as well as to evaluate the relationship of these markers with the risk of recurrence after surgical treatment. Methods : we studied a historical cohort of 94 women with intraepithelial lesions CIN I (low grade), CIN II and CIN III (high grades) submitted to conization or electrosurgical excision of the transformation zone. We evaluated all surgical specimens for immunohistochemical expression of p16ink4a, hTert and Ki67. Results : the mean age was 38.2 years; p16ink4a was absent in most CIN I cases. In patients with CIN II or I/II (association of low and high-grade lesions), we observed p16ink4a ≤10%. In patients with CIN III, we found a higher expression frequency of p16ink4a >50%. In CIN I, the majority had Ki67≤10% and low frequency of Ki67>50%. In the CIN III category, there were fewer patients with Ki67≤10%, and Ki67 was absent in most patients of CIN II and III groups. There was no association between hTert expression and histologic grade. There were no statistically significant differences between the expression of the markers in patients with and without recurrence. Conclusion : there was a statistically significant association of p16ink4a and Ki67 with histological grade. The markers' expression, as for disease recurrence, was not statistically significant in the period evaluated.


RESUMO Objetivo: estudar a associação entre a graduação histológica das neoplasias intraepiteliais cervicais (NIC I, NIC II e NIC III) e a expressão imuno-histoquímica para p16ink4a, hTert e Ki67, assim como, avaliar a relação destes marcadores com o risco de recorrência após tratamento cirúrgico. Métodos: estudo de coorte histórica de 94 mulheres portadoras de lesões intraepiteliais NIC I (baixo grau), NIC II e NIC III (altos graus), submetidas à conização ou à excisão eletrocirúrgica da zona de transformação. Todas as peças cirúrgicas foram avaliadas quanto à expressão imuno-histoquímica para p16ink4a, hTert e Ki67. Resultados: a média de idade das pacientes foi 38,2 anos. Nas pacientes NIC I, a p16ink4a estava ausente na maioria dos casos; nas pacientes NIC II ou I/II (associação de lesões de baixo e alto graus), observou-se frequência de p16ink4a≤10%. Nas pacientes NIC III, observou-se maior frequência de expressão de p16ink4a>50%. Na categoria NIC I, a maioria apresentava Ki67≤10% e baixa frequência de Ki67>50%. Na categoria NIC III houve menor número de pacientes com Ki67≤10%, sendo que a maior parte das pacientes tinha Ki67 ausente nos grupos NIC II e III. Não houve associação entre a expressão do marcador imuno-histoquímico hTert e a graduação histológica. Não houve diferenças estatisticamente significativas entre as expressões dos marcadores em pacientes com e sem recorrência. Conclusão: houve associação estatisticamente significativa apenas de p16ink4a e Ki67 com a graduação histológica. A expressão dos marcadores em relação à recorrência da doença não foi estatisticamente significativa no período avaliado.


Assuntos
Humanos , Feminino , Adulto , Neoplasia Intraepitelial Cervical/metabolismo , Telomerase/biossíntese , Antígeno Ki-67/biossíntese , Inibidor p16 de Quinase Dependente de Ciclina/biossíntese , Neoplasia Intraepitelial Cervical/patologia , Gradação de Tumores
13.
Mol Med Rep ; 15(4): 2049-2056, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28260047

RESUMO

Focal cortical dysplasia (FCD) is caused by numerous alterations, which can be divided into abnormalities of the cortical architecture and cytological variations; however, the exact etiology of FCD remains unknown. The generation of induced pluripotent stem cells (iPSCs) from the cells of patients with neurological diseases, and their subsequent tissue­specific differentiation, serves as an invaluable source for testing and studying the initial development and subsequent progression of diseases associated with the central nervous system. A total of 2 patients demonstrating seizures refractory to drug treatment, characterized as FCD Type IIb, were enrolled in the present study. Fibroblasts were isolated from residual skin fragments obtained from surgical treatment and from brain samples obtained during surgical resection. iPSCs were generated following exposure of fibroblasts to viral vectors containing POU class 5 homeobox 1 (OCT4), sex determining region Y­box 2 (SOX2), Kruppel­like factor 4 and c­MYC genes, and were characterized by immunohistochemical staining for the pluripotent markers homeobox protein NANOG, SOX2, OCT4, TRA1­60 and TRA1­81. The brain samples were tested with antibodies against protein kinase B (AKT), phosphorylated­AKT, mechanistic target of rapamycin (mTOR) and phosphorylated­mTOR. Analysis of the AKT/mTOR pathway revealed a statistically significant difference between the cerebral tissues of the two patients, which were of different ages (45 and 12 years old). Clones with the morphological features of embryonic cells were detected on the 13th day and were characterized following three subcultures. The positive staining characteristics of the embryonic cells confirmed the successful generation of iPSCs derived from the patients' fibroblasts. Therefore, the present study presents a method to obtain a useful cellular source that may help to understand embryonic brain development associated with FCD.


Assuntos
Epilepsia/patologia , Células-Tronco Pluripotentes Induzidas/patologia , Malformações do Desenvolvimento Cortical do Grupo I/patologia , Células Cultivadas , Reprogramação Celular , Criança , Epilepsia/metabolismo , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Masculino , Malformações do Desenvolvimento Cortical do Grupo I/metabolismo , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
14.
Clin Oral Investig ; 21(1): 199-210, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26955837

RESUMO

OBJECTIVE: This study aimed to investigate the effect of hyperbaric oxygen therapy (HBOT) on tooth extraction sites in rats treated with bisphosphonate. MATERIALS AND METHODS: Rats were treated with zoledronic acid, subjected to tooth extractions and allocated into groups: (1) 7 days of HBOT, (2) 14 days of HBOT, (3) 7-day control, and (4) 14-day control. The site of tooth extractions was analyzed by histomorphometry and immunohistochemistry. RESULTS: On macroscopic analysis, HBOT did not significantly affect bone exposure volume either at 7 or 14 days. On hematoxylin and eosin (H&E) analysis, the 14-day HBOT group showed less non-vital bone compared to both controls and 7-day HBOT group. HBOT significantly lowered expression of vascular endothelial growth factor (VEGF), receptor activator NF-kB ligand (RANKL), bone morphogenetic protein-2 (BMP-2), and osteoprotegerin (OPG) at 7 days, compared to control, whereas at 14 days, there was no significant difference for these variables. CONCLUSION: HBOT can reduce the amounts of non-vital bone microscopically detected in tooth extraction sites of rats subjected to bisphosphonate therapy. The effect seems to occur in a dose-dependent mode. Further studies are required to clarify the mechanisms accounting for this effect. CLINICAL RELEVANCE: Treatment of bisphosphonate-related osteonecrosis of the jaw (BRONJ) has been a challenging task, where the effectiveness of HBOT is controversial. This study reports important effects of HBOT on the maxillae of rats subjected to bisphosphonate treatment, making an important contribution to the knowledge about the applicability of HBOT in BRONJ.


Assuntos
Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/prevenção & controle , Conservadores da Densidade Óssea/farmacologia , Difosfonatos/farmacologia , Oxigenação Hiperbárica , Imidazóis/farmacologia , Extração Dentária , Animais , Osteonecrose da Arcada Osseodentária Associada a Difosfonatos/metabolismo , Proteína Morfogenética Óssea 2/metabolismo , Imuno-Histoquímica , Osteoprotegerina/metabolismo , Ligante RANK/metabolismo , Ratos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ácido Zoledrônico
15.
Mol Neurobiol ; 54(10): 7869-7882, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27848207

RESUMO

This study investigated the role of kinins and their receptors in malignant brain tumors. As a first approach, GL-261 glioma cells were injected (2 × 105 cells in 2 µl/2 min) into the right striatum of adult C57/BL6 wild-type, kinin B1 and B2 receptor knockout (KOB1R and KOB2R) and B1 and B2 receptor double knockout mice (KOB1B2R). The animals received the selective B1R (SSR240612) and/or B2R (HOE-140) antagonists by intracerebroventricular (i.c.v.) route at 5, 10, and 15 days. The tumor size quantification, mitotic index, western blot analysis, quantitative autoradiography, immunofluorescence, and confocal microscopy were carried out in brain tumor samples, 20 days after tumor induction. Our results revealed an uncontrolled tumor growing in KOB1R or SSR240612-treated mice, which was blunted by B2R blockade with HOE-140, suggesting a crosstalk between B1R and B2R in tumor growing. Combined treatment with B1R and B2R antagonists normalized the upregulation of tumor B1R and decreased the tumor size and the mitotic index, as was seen in double KOB1B2R. The B1R was detected on astrocytes in the tumor, indicating a close relationship between this receptor and astroglial cells. Noteworthy, an immunohistochemistry analysis of tumor samples from 16 patients with glioma diagnosis revealed a marked B1R immunopositivity in low-grade gliomas or in older glioblastoma individuals. Furthermore, the clinical data revealed a significantly higher immunopositivity for B1R, when compared to a lower B2R immunolabeling. Taken together, our results show that blocking simultaneously both kinin receptors or alternatively stimulating B1R may be of therapeutic value in the treatment of brain glioblastoma growth and malignancy.


Assuntos
Neoplasias Encefálicas/patologia , Glioma/patologia , Receptor B1 da Bradicinina/metabolismo , Receptor B2 da Bradicinina/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Bradicinina/análogos & derivados , Bradicinina/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Dioxóis/farmacologia , Glioma/tratamento farmacológico , Camundongos , Camundongos Knockout , Receptor B1 da Bradicinina/genética , Receptor B2 da Bradicinina/genética , Sulfonamidas/farmacologia , Regulação para Cima/efeitos dos fármacos
16.
Toxicol Res (Camb) ; 5(1): 168-179, 2016 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30090335

RESUMO

Nanotoxicology aims to study the safety of nanomaterials, especially towards human exposure. Biodegradable polymeric nanocapsules have been indicated as potential drug carriers applicable for treating several pathologies. Thus, the objective of this study was to evaluate the potential cardiotoxicity of biodegradable lipid-core nanocapsules (LNC) containing poly(ε-caprolactone). Nanocapsules were characterized and the acute toxicity evaluation was conducted in Wistar rats. Two control groups (saline and tween/glycerol) were utilized, and three treated groups were chosen for low, intermediate and high doses: 28.7 × 1012 (LNC-1), 57.5 × 1012 (LNC-2) and 115 × 1012 (LNC-3), expressed as number of nanocapsules per milliliter per kg. Blood pressure measurements were performed in non-anesthetized animals by caudal plethysmography. The electrocardiographic (ECG) and echocardiographic analyses were carried out after anesthesia by isoflurane at two points, prior to treatment and after 14 days. Blood was collected 24 hours and 14 days after treatment. Biochemical and histopathological analyses were performed. During the evaluation period, no deaths, weight loss or clinical signs were observed. Post-treatment systolic pressures (24 h and 14 days) were significantly increased in comparison to pre-treatment in both control groups and treated groups, which is suggested to be as a possible consequence of the infused volume. Serum sodium, potassium, aspartate aminotransferase and alkaline phosphatase, as well as, hematological parameters were within reference values established for rats. ECG showed no indications of cardiotoxicity. Despite the echocardiograms, no alterations in the ejection fraction were found as indicators of cardiotoxicity. Cardiac histopathology also demonstrated no alterations. Therefore, the present results on acute evaluation after i.v. administration, by slow infusion, showed potential safety since no cardiotoxic effects by ECG, echocardiographic, arterial pressure, biochemical and histopathological analyses were found.

17.
World J Gastroenterol ; 20(32): 11406-14, 2014 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-25170229

RESUMO

AIM: To evaluate preventative effects of glutamine in an animal model of gut ischemia/reperfusion (I/R). METHODS: Male Wistar rats were housed in a controlled environment and allowed access to food and water ad libitum. Twenty male Wistar rats were divided into four experimental groups: (1) control group (control) - rats underwent exploratory laparotomy; (2) control + glutamine group (control-GLU) - rats were subjected to laparotomy and treated intraperitoneally with glutamine 24 and 48 h prior to surgery; (3) I/R group - rats were subjected to occlusion of the superior mesenteric artery for 30 min followed by 15 min of reperfusion; and (4) ischemia/reperfusion + glutamine group (G + I/R) - rats were treated intraperitoneally with glutamine 24 and 48 h before I/R. Local and systemic injuries were determined by evaluating intestinal and lung segments for oxidative stress using lipid peroxidation and the activity of superoxide dismutase (SOD), interleukin-6 (IL-6) and nuclear factor kappa beta (NF-κB) after mesenteric I/R. RESULTS: Lipid peroxidation of the membrane was increased in the animals subjected to I/R (P < 0.05). However, the group that received glutamine 24 and 48 h before the I/R procedure showed levels of lipid peroxidation similar to the control groups (P < 0.05). The activity of the antioxidant enzyme SOD was decreased in the gut of animals subjected to I/R when compared with the control group of animals not subjected to I/R (P < 0.05). However, the group that received glutamine 24 and 48 h before I/R showed similar SOD activity to both control groups not subjected to I/R (P < 0.05). The mean area of NF-κB staining for each of the control groups was similar. The I/R group showed the largest area of staining for NF-κB. The G + I/R group had the second highest amount of staining, but the mean value was much lower than that of the I/R group (P < 0.05). For IL-6, control and control-GLU groups showed similar areas of staining. The I/R group contained the largest area of IL-6 staining, followed by the G + I/R animals; however, this area was significantly lower than that of the group that underwent I/R without glutamine (P < 0.05). CONCLUSION: These results demonstrate that pretreatment with glutamine prevents mucosal injury and improves gut and lung recovery after I/R injury in rats.


Assuntos
Antioxidantes/farmacologia , Glutamina/farmacologia , Intestinos/irrigação sanguínea , Intestinos/efeitos dos fármacos , Pulmão/irrigação sanguínea , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Interleucina-6/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Intestinos/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Lesão Pulmonar/metabolismo , Lesão Pulmonar/patologia , Lesão Pulmonar/prevenção & controle , Masculino , NF-kappa B/metabolismo , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo , Mucosa Respiratória/patologia , Superóxido Dismutase/metabolismo , Fatores de Tempo
18.
Naunyn Schmiedebergs Arch Pharmacol ; 387(9): 837-48, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24908156

RESUMO

Oxaliplatin (OXA) is a platinum compound widely used in the treatment of some solid tumors, especially colorectal cancer. Despite its usefulness, oxaliplatin-associated neurotoxicity represents the main dose-limiting factor of this drug, and until now, there is no suitable treatment. Chemotherapy with oxaliplatin also increases the rate of developing hepatic damages with inflammatory activity, termed chemotherapy-associated steatohepatitis (CASH). In the present study, we aimed to compare the effects of a series of antioxidant compounds on simultaneous development of oxaliplatin-induced hepato- and neurotoxicity in mice. Mice BALB/c were treated with oxaliplatin for 6 weeks, 10 mg/kg, intraperitoneally, resulting in mechanical allodynia and hepatic steatosis. We administered the following antioxidant compounds--rutin (RT) (20 mg/kg), resveratrol (RVS) (100 mg/kg), quercetin (QT) (20 mg/kg), and quercetin nanoemulsion (NQT) (20 mg/kg)--daily by gavage to BALB/c, and N-acetylcysteine (NAC) was used as positive control. Treatments with RSV, RUT, or NQT were able to prevent mechanical allodynia when compared to the OXA group, and this effect was associated with decreased c-Fos immunopositivity in the lumbar spinal cord. Regarding the effects on steatohepatitis, RVS, QT, and NQT almost completely reversed the mean liver weight increase induced by OXA. In accordance with these previous data, histological evaluation indicated attenuation of all features of hepatic steatosis evaluated in RSV, RUT, QT, and NQT groups. These compounds were able to reduce the immunopositivity for the apoptosis marker caspase-3. On the other hand, only QT and NQT treatments were able to reduce neutrophil migration measured by myeloperoxidase (MPO) activity. These results suggest that the compounds tested, RSV, RUT, QT, and NQT, would be useful for the clinical treatment of neuro- and hepatoxicity induced by oxaliplatin.


Assuntos
Fígado Gorduroso/tratamento farmacológico , Síndromes Neurotóxicas/tratamento farmacológico , Compostos Organoplatínicos , Quercetina/uso terapêutico , Rutina/uso terapêutico , Estilbenos/uso terapêutico , Alanina Transaminase/sangue , Animais , Antineoplásicos , Aspartato Aminotransferases/sangue , Caspase 3/metabolismo , Emulsões , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Hiperalgesia/tratamento farmacológico , Vértebras Lombares , Masculino , Camundongos Endogâmicos BALB C , Síndromes Neurotóxicas/metabolismo , Oxaliplatina , Peroxidase/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Quercetina/farmacologia , Resveratrol , Rutina/farmacologia , Medula Espinal/metabolismo , Estilbenos/farmacologia
19.
Clin Neurol Neurosurg ; 120: 32-5, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24731572

RESUMO

OBJECTIVES: Skull base meningiomas are a neurosurgical challenge due to the involvement of neurovascular structures. In this study, the authors present the first study of the trans-operative use of sodium fluorescein (SF) to enhance skull base meningiomas and perform a quantitative digital analysis of the tumors' pigmentation. The goal of the study was to observe the SF enhancement of skull base meningiomas. PATIENTS AND METHODS: A prospective, within-subjects study was designed and performed. This study included twelve patients with skull base meningiomas. After an initial dissection, digital pictures were taken before and after systematic injections of SF using the same light-source used for the surgical microscope. These pictures were analyzed with software that calculated the wavelengths of the sodium fluorescein before and after the injection of the dye. RESULTS: The meningiomas in the sample included the following types: 1 cavernous sinus, 1 olfactory groove, 3 petroclival, 1 tuberculum sellae, 3 sphenoid wings, 1 anterior clinoid, and 2 temporal floor. The SF enhancement in all tumors was strongly positive. CONCLUSIONS: The low cost, universal availability and safety of SF indicate that this dye should be examined in further studies, and its applications in skull-base meningioma surgeries should be further assessed.


Assuntos
Meios de Contraste , Angiofluoresceinografia/métodos , Fluoresceína , Meningioma/diagnóstico por imagem , Neoplasias da Base do Crânio/diagnóstico por imagem , Meios de Contraste/administração & dosagem , Fluoresceína/administração & dosagem , Humanos , Meningioma/irrigação sanguínea , Meningioma/cirurgia , Radiografia , Neoplasias da Base do Crânio/irrigação sanguínea , Neoplasias da Base do Crânio/cirurgia
20.
Surg Neurol Int ; 5: 3, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24575318

RESUMO

BACKGROUND: The resection of the meningiomas surrounding the dura is an important goal during the removal of a convexity meningioma. The authors present the first application of sodium fluorescein (SF) as a tool for tumor and dural tail identification in convexity meningiomas. METHODS: Five frontal convexity meningiomas operated on between December 2012 and April 2013 were included. After initial dissection a dose of 1 g of the SF, 20% was injected into a peripheral vein. Tumor and dural tail were removed using the correlation between magnetic resonance imaging (MRI) findings and transoperative SF enhancement. RESULTS: Simpson Grade 1 removal was obtained in three cases, grade 2 in one atypical meningioma and grade zero in one case. SF dural tail enhancement was positive in all cases and histologic analysis evidenced involvement of the dura by tumors. CONCLUSION: SF enhancement was evident in meningiomas and dura surrounding the lesions. Histologic analysis confirmed dural involvement. SF could represent an universally available fluorescent tool for meningioma surgery.

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