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1.
Enferm. infecc. microbiol. clín. (Ed. impr.) ; 33(4): 248-252, abr. 2015. tab
Artigo em Inglês | IBECS | ID: ibc-136739

RESUMO

AIM: of the study To determine the activity of fluoroquinolones (FQ) and the selection of FQ-resistant mutants in a macrophage experimental infection model (MEIM). MATERIAL AND METHODS: Canine macrophages were inoculated with Brucella melitensis ATCC 23457 (WT), achieving intracellular counts of around 105 CFU/mL. Cell cultures were incubated in the presence of ciprofloxacin (CIP), levofloxacin (LEV), moxifloxacin (MOX), and doxycycline (DOX). After cell lysis, surviving microorganisms were plated for count purposes, and plated onto antibiotics-containing media for mutant selection. Topoisomerases mutations were detected by PCR and sequencing. RESULTS: Bacterial counts after cell lysis were 14.3% (CIP), 65.3% (LEV), and 75% (MOX) lower compared to the control. Quinolone-resistant mutants emerged in cell cultures containing CIP and LEV with a frequency of around 0.5 × 10-3. All mutants showed an Ala87Val change in GyrA. Mutants had FQs MICs around 10 × WT. The ability of these mutants for infecting new macrophages and the intracellular lysis after antibiotic exposure did not change significantly. No 2nd step FQ-resistant mutants were selected from 1st step mutants. CONCLUSIONS: Intracellular activity of FQs is low against WT and gyrA-mutant Brucella. FQs easily select gyrA mutants in MEIM. The ability of mutants for infecting new macrophages remains unchanged. In this MEIM, 2nd step mutants do not emerge


OBJETIVO: del estudio Conocer la actividad de fluoroquinolonas (FQ) y la selección de mutantes resistentes (MR) a FQ en un modelo experimental de infección en macrófagos. MATERIAL Y MÉTODOS: Se inocularon macrófagos de origen canino con la cepa tipo Brucella melitensis ATCC 23457 (CT) hasta alcanzar recuentos intracelulares de aproximadamente 105 UFC/mL. Los cultivos celulares fueron incubados en presencia de ciprofloxacino, levofloxacino, moxifloxacino y doxiciclina. Una vez lisadas las células, los microorganismos supervivientes fueron sembrados en placas sin antibiótico para recuento, y en medios de cultivo conteniendo antimicrobianos para selección de MR. Los MR a topoisomerasas se caracterizaron mediante PCR y secuenciación. RESULTADOS: Los recuentos de microorganismos supervivientes tras el tratamiento con FQ y la lisis celular fueron: 14,3% ciprofloxacino, 65,3% levofloxacino y 75% moxifloxacino con respecto al control. Se seleccionaron MR a FQ en los cultivos celulares que contenían ciprofloxacino y levofloxacino, con una frecuencia en torno a 0,5 × 10-3. Todos los MR seleccionados portaban un cambio Ala87Val en gyrA, y mostraban CIM de FQ en torno a 10x la de la CT. La capacidad de estos MR para infectar nuevos macrófagos y su lisis intracelular tras tratamiento antibiótico no se modificaron de manera significativa con respecto a la CT. Usando la misma metodología, no se seleccionaron MR de segundo nivel a partir de los MR de primer nivel obtenidos. CONCLUSIONES: La actividad intracelular de FQ frente a Brucella es baja, tanto frente a la CT como frente a mutantes con cambios en gyrA. Las FQ seleccionan con facilidad mutantes con cambios en gyrA en este modelo experimental de infección en macrófagos. La capacidad de estos mutantes para infectar nuevos macrófagos permanece intacta. En este modelo experimental de infección en macrófagos no se observó la selección de mutantes de segundo nivel


Assuntos
Humanos , Quinolonas/farmacocinética , Brucella/patogenicidade , Brucelose/tratamento farmacológico , Fluoroquinolonas/farmacocinética , Macrófagos , Resistência Microbiana a Medicamentos , DNA Topoisomerases Tipo II , Modelos Animais de Doenças
2.
Rev. esp. patol ; 46(1): 14-25, ene.-mar. 2013. tab, ilus
Artigo em Espanhol | IBECS | ID: ibc-109147

RESUMO

Diversos estudios con un largo periodo de seguimiento muestran que la tasa de recidiva para los meningiomas grado I (benignos) y II (atípicos) se sitúa entre el 15-25% y el 30-35% respectivamente, a pesar de una cirugía agresiva. Hemos investigado 135 meningiomas completamente resecados para identificar y comparar marcadores pronósticos de recurrencia tumoral. Hemos determinado la expresión inmunohistoquímica de 30 biomarcadores, la muerte celular por apoptosis mediante un ensayo de hibridación in situ (ApopDETEKTM) y las perdidas en el cromosoma 1p36 mediante FISH. El análisis estadístico univariante mostró que el grado tumoral de la OMS, la alta celularidad, la atipia nuclear, las pérdidas en el cromosoma 1p36 (determinadas en 20 de los 107 casos válidos) y la expresión de COX-2 (9 casos positivos y 126 negativos), Ciclina A, Topoisomerasa II y MIB1/Ki67 se asociaron con el periodo libre de recurrencia. El análisis multivariante de estas variables pronósticas reveló que solamente las pérdidas en el cromosoma 1p36 y la expresión de COX-2 y MIB1 eran factores independientes para la predicción de recidiva tumoral. El análisis estadístico para la covariación de COX-2 y las perdidas en 1p36 mostraron un efecto antagonista para ambos marcadores. Los meningiomas con pérdidas en 1p36 mostraron un incremento significativo de la necrosis, la atipia nuclear y la expresión de Ciclina E, PAKT, PDGF y p21. La sobreexpresión de COX-2 se asocia a su vez con un aumento de la expresión de VEGF, PDGF, HER2 y MDM2. Los inhibidores selectivos de COX-2 podrían ser usados como un tratamiento quimiopreventivo putativo para evitar la recurrencia en aquellos meningiomas con sobreexpresión de COX-2(AU)


Long follow-up studies show that the 10-year regrowth rate for grade I (benign) and II (atypical) meningiomas rises up to 15---25% and 30---35%, respectively, despite aggressive surgery. We investigated completely removed meningiomas grade I and II (n = 135) to identify and compare prognostic markers for tumour recurrence. We determined the immunohistochemical expression of 30 biomarkers, cell death assay by in situ hybridisation (ApopDETEKTM) and loss of chromosome 1p36 by FISH. The univariate statistical analysis showed that WHO grade, high cellularity, nuclear atypia, loss of 1p36 (determined in 20 out of 107 valid cases), expression of COX-2 (9 positive cases and 126 negative cases), Cyclin A, Topoisomerase II and MIB1/ki67 were associated with recurrence-free survival. The multivariate linkage analysis for the prognostic variables revealed that only 1p36 loss, expression of COX-2 and MIB1 were independent factors for predicting meningioma recurrence. The statistical analysis of COX-2 and 1p36 loss co-variation showed an antagonistic effect for both prognostic markers. Meningiomas with 1p36 loss showed significant increase of necrosis, nuclear atypia and increased expression of Cyclin E, PAKT, PDGF and p21. COX-2 overexpression was associated with increased VEGF, PDGF, HER2 and MDM2 expression. COX-2 inhibitors may be used as a putative chemopreventive treatment for meningioma recurrence in tumours with COX-2 over-expression(AU)


Assuntos
Humanos , Masculino , Feminino , Meningioma/diagnóstico , Meningioma/patologia , Imuno-Histoquímica/métodos , Imuno-Histoquímica , Recidiva Local de Neoplasia/patologia , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/isolamento & purificação , Análise de Variância , Prognóstico , Apoptose , Proteína de Suscetibilidade a Apoptose Celular , DNA Topoisomerases Tipo II , Inibidores da Topoisomerase II , Estudos Retrospectivos , Cromossomos , Cromossomos
3.
Clin. transl. oncol. (Print) ; 14(3): 163-168, mar. 2012. tab, ilus
Artigo em Inglês | IBECS | ID: ibc-126171

RESUMO

Anthracyclines are frequently used in the adjuvant setting for breast cancer treatment since it is considered that anthracycline-based chemotherapy treatment benefits breast cancer patients. Nonetheless, these drugs are associated with severe side effects and predictive factors, for sensitivity to anthracyclines, are warranted in clinical practice. Topoisomerase 2 alpha (TOP2A) is considered to be the molecular target of these drugs. The potential predictive value of TOP2A amplification and overexpression has been extensively studied in breast cancer patients treated with anthracyclines. However, results are not conclusive. In this paper, we review some of the published studies addressing the predictive value of TOP2A as well as the cellular functions of this enzyme and its status in breast cancer tissue (AU)


Assuntos
Animais , Feminino , Antraciclinas/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/diagnóstico , Antígenos de Neoplasias/fisiologia , DNA Topoisomerases Tipo II/fisiologia , Modelos Biológicos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/fisiologia , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/metabolismo , Antineoplásicos/uso terapêutico , Biomarcadores Farmacológicos/análise , Biomarcadores Farmacológicos/metabolismo , Carcinoma/diagnóstico , Carcinoma/tratamento farmacológico , DNA Topoisomerases Tipo II/genética , DNA Topoisomerases Tipo II/metabolismo , Proteínas de Ligação a DNA/genética
4.
Clin. transl. oncol. (Print) ; 12(1): 8-14, ene. 2010. ilus
Artigo em Inglês | IBECS | ID: ibc-123878

RESUMO

Therapy-related leukaemias are becoming an increasing healthcare problem as more patients survive their primary cancers. The nature of the causative agent has an important bearing upon the characteristics, biology, time to onset and prognosis of the resultant leukaemia. Agents targeting topoisomerase II induce acute leukaemias with balanced translocations that generally arise within 3 years, often involving the MLL, RUNX1 and RARA loci at 11q23, 21q22 and 17q21 respectively. Chromosomal breakpoints have been found to be preferential sites of topoisomerase II cleavage, which are believed to be repaired by the nonhomologous end-joining DNA repair pathway to generate chimaeric oncoproteins that underlie the resultant leukaemias. Therapy-related acute myeloid leukaemias occurring after exposure to antimetabolites and/or alkylating agents are biologically distinct with a longer latency period, being characterised by more complex karyotypes and loss of p53. Although treatment of therapy-related leukaemias represents a considerable challenge due to prior therapy and comorbidities, curative therapy is possible, particularly in those with favourable karyotypic features (AU)


Assuntos
Humanos , Animais , Masculino , Feminino , Leucemia Mielomonocítica Aguda/genética , Segunda Neoplasia Primária/induzido quimicamente , Segunda Neoplasia Primária/genética , Biologia Molecular/métodos , Antineoplásicos Alquilantes/efeitos adversos , Quebra Cromossômica , Reparo do DNA , Reparo do DNA/genética , DNA Topoisomerases Tipo II/genética , DNA Topoisomerases Tipo II/metabolismo , DNA Topoisomerases Tipo II/fisiologia , Leucemia Mielomonocítica Aguda/induzido quimicamente , Modelos Biológicos
5.
Clin. transl. oncol. (Print) ; 11(8): 548-551, ago. 2009. ilus
Artigo em Inglês | IBECS | ID: ibc-123674

RESUMO

INTRODUCTION: The expression of E-cadherin, beta-catenin and topoisomerase II has been associated with clinical outcome of several cancers including sarcomas. We aimed to evaluate the expression of these markers in leiomyosarcomas (LMS). MATERIALS AND METHODS: Paraffin blocks of 19 primary, nonmetastatic LMS were analysed immunohistochemically for the expression of the above-mentioned markers with a cutoff level for positivity of 20% of cell staining. RESULTS: Expression of E-cadherin was negative in all LMS. Nuclear expression of beta-catenin was also negative in all cases, while positive cytoplasmic beta-catenin expression was observed in approximately half of the patients. The majority of LMS had expression of topoisomerase IIalpha, although only in 10 patients was this expression in more than 20% of tumour cells. From the analysed factors, tumour size was statistically significantly correlated with relapse-free survival. CONCLUSIONS: Further evidence with larger series is required in order to determine the implication of these markers in LMS (AU)


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Caderinas/metabolismo , Antígenos de Neoplasias/metabolismo , DNA Topoisomerases Tipo II/metabolismo , Leiomiossarcoma/metabolismo , beta Catenina/metabolismo , Proteínas de Ligação a DNA/metabolismo , Imuno-Histoquímica/métodos , Imuno-Histoquímica , Leiomiossarcoma/patologia
6.
Clin. transl. oncol. (Print) ; 11(1): 54-59, ene. 2009.
Artigo em Inglês | IBECS | ID: ibc-123576

RESUMO

INTRODUCTION: To evaluate the sequential administration of doxorubicin (A) and cyclophosphamide (C) followed by weekly docetaxel in women with stage II to IIIA breast cancer. PATIENTS AND METHODS: Patients received 60 mg/m(2) of A and 600 mg/m(2) of C every three weeks for four cycles followed by 12 infusions of weekly docetaxel at a dose of 36 mg/m(2) and with a 2-week resting period. RESULTS: Sixty-three women were included. On an intention-to- treat basis, clinical response rate was 90% (95% CI: 83-98), with 46% complete responses. Breast-conserving surgery could be performed in 43 patients (68%). Complete pathological responses in the breast were confirmed in 17% of patients. No correlations between levels of expression of topoisomerase II alpha, survivin or p27 and the pathological response were detected. The study treatment was generally well tolerated. CONCLUSION: Neoadjuvant AC followed by weekly docetaxel is a feasible regimen for patients with early-stage breast cancer (AU)


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Assuntos
Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Estudos Multicêntricos como Assunto , Ensaios Clínicos Fase II como Assunto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Terapia Neoadjuvante/métodos , DNA Topoisomerases Tipo II/biossíntese , Antígenos de Neoplasias/biossíntese , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Imuno-Histoquímica , Proteínas Associadas aos Microtúbulos/biossíntese
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