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El estudio tuvo como objetivo realizar una revisión sistemática, con el fin de mapear la asociación entre la aptitud cardiorrespiratoria, el tiempo de pantalla y el estado de peso en niños y adolescentes, así como verificar la dirección de estas relaciones. La búsqueda se realizó de acuerdo con las recomendaciones de PRISMA, en las bases de datos Web of Science, Scopus y Medline. Se incluyeron estudios completos y originales, publicados entre 2000 y marzo de 2021, que evaluaban las variables citadas en conjunto y / o asociaciones. Se identificaron 152 artículos y, después del refinamiento según los resultados, se evaluaron cualitativamente 30 documentos. Se puede observar que las variables de salud, como aptitud cardiorrespiratoria, tiempo de pantalla y estado de peso, continúan con datos negativamente alarmantes en esta población, y que están fuertemente correlacionadas, demostrando que la modificación de una de ellas puede interferir con las otras. mejorando así el estado de salud de niños y adolescentes.(AU)
O estudo teve como objetivo realizar uma revisão sistemática, com intuito de mapear as relações entre aptidão cardiorrespiratória, tempo de tela eestado nutricional em crianças e adolescentes, bem como verificar qual a direção dessas relações. A busca foi realizada de acordo com as recomendaçõesPRISMA, nas bases de dados Web of Science, Scopus, e no Medline. Foram incluídos estudos completos e originais, publicados entre 2000 e março de 2023,e que avaliassem as variáveis citadas de forma concomitante e/ou associações. Foram identificados 210 artigos, e após refinamento conforme desfechos,34 documentos avaliados de forma qualitativa. Pode-se verificar que as variáveis de saúde, como aptidão cardiorrespiratória, tempo de tela e estadonutricional, seguem com dados negativamente alarmantes nesta população, e que elas estão correlacionadas fortemente, demonstrando que amodificação de uma delas pode vir a interferir nas demais, melhorando assim o status de saúde de crianças e adolescentes.(AU)
The study aimed to carry out a systematic review, with the aim of mapping the relationships between cardiorespiratory fitness, screen time andnutritional status in children and adolescents, as well as verifying the direction of these relationships. The search was carried out according to thePRISMA recommendations, in the Web of Science, Scopus, and Medline databases. Complete and original studies, published between 2000 and March2023, that evaluated the variables cited concomitantly and / or associations were included. 210 articles were identified, and after refinement accordingto outcomes, 34 documents were evaluated qualitatively. It can be seen that the health variables, such as cardiorespiratory fitness, screen time andweight status, continue with negatively alarming data in this population, and that they are strongly correlated, demonstrating that the modification of oneof them may interfere with the others , thus improving the health status of children and adolescents.(AU)
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Humanos , Masculino , Femenino , Niño , Adolescente , Obesidad Infantil , Tiempo de Pantalla , Esfuerzo Físico , Fatiga , Salud Infantil , Obesidad , Medicina DeportivaRESUMEN
The Steering Committee for Post-accident Management Preparedness (CODIRPA) was commissioned by the French Government in 2005 with the aim of establishing the main principles to be set up for population protection and recovery in the long term. From the beginning, one of the main principles was the pluralistic nature of the working groups (WGs), including scientific and technical experts, representatives from state departments, nuclear operators, and representatives of civil society (i.e. stakeholders). Stakeholders were mainly associated with the various WGs of CODIRPA. In order to foster the involvement of stakeholders from civil society in the works of CODIRPA, a new organisation was implemented with two WGs: one mainly composed of technical experts for tackling technical issues, and one for evaluating the proposals made by the experts from the stakeholders' point of view. This article presents the results of this new strategy.
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Protección Radiológica , AccidentesAsunto(s)
Antibacterianos/administración & dosificación , Profilaxis Antibiótica/métodos , Infección de la Herida Quirúrgica/prevención & control , Adulto , Anciano , Anciano de 80 o más Años , Antibacterianos/efectos adversos , Profilaxis Antibiótica/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Readmisión del Paciente/estadística & datos numéricos , Estudios Retrospectivos , Infección de la Herida Quirúrgica/epidemiología , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Antimicrobial stewardship can be challenging in children with bloodstream infections (BSIs) caused by Gram-negative bacilli (GNB). This retrospective cohort study explored how data elements in the electronic health record could potentially optimize empiric antibiotic therapy for BSIs caused by GNB, via the construction of customized antibiograms for categorical GNB infections and identification of opportunities to minimize organism-drug mismatch and decrease time to effective therapy. Our results suggest potential strategies that could be implemented at key decision points in prescribing at initiation, modification, and targeting of therapy.
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Antibacterianos/uso terapéutico , Infecciones por Bacterias Gramnegativas/diagnóstico , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Sepsis/tratamiento farmacológico , Programas de Optimización del Uso de los Antimicrobianos/estadística & datos numéricos , Niño , Preescolar , Humanos , Pruebas de Sensibilidad Microbiana , Estudios RetrospectivosRESUMEN
Overweight and obesity are associated with chronic and subclinical inflammation due to an imbalance of inflammatory mediators. However, the association with gene polymorphism has been rarely studied in children. The aim of this study was to determine if serum concentrations of C-reactive protein (CRP) and interleukin-6 (IL-6) are related to the IL6 rs1800795, IL6 rs2069845 and CRP rs1205 polymorphisms (SNPs) according to body mass index (BMI) in a sample of children and adolescents. A cross-sectional study in 470 students between 7 and 17yearsof age of anthropometric characteristics, high sensitivity-CRP (Hs-CRP) and IL-6 levels and three SNPs genotyped. The prevalence ratio of hs-CRP>3mg/L in obese individuals was 4.15 (CI 2.43-7.06; p=0.01), and it was 1.91 (CI 1.03-3.55; p=0.03) in overweight individuals and 1.74 (CI 1.05-2.88 p=0.03) in females. Individuals with waist circumference (WC) and body fat percentage (BF%) alterations showed elevated levels of hs-CRP (p=4.3×10-5 and p=5.3×10-6). The combination of any two anthropometric measurement increases CRP levels, especially combinations with obesity body mass index (BMI): BMI+WC and BMI+BF%. Among the overweight/obesity group, T allele carriers of CRP rs1205 showed lower levels of hs-CRP (0.5, IQR=0.3-1.8mg/L) than CC homozygotes (1.5, IQR=0.4-3.4mg/L, p=0.018). Additionally, considering subjects with two or three anthropometric alterations for CRP rs1205: rs1205 T allele carriers had lower levels of hs-CRP (0.7, IQR=0.3-2.7mg/L) than CC homozygotes (1.2, IQR=0.5-3.5mg/L, p=0.02). In conclusion, carriers of the rs1205/T allele with higher BMIs had lower levels of hs-CRP. Schoolchildren who were overweight/obese had higher levels of CRP and IL-6, whereas individuals with WC and BF% alterations had higher levels of CRP.
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Índice de Masa Corporal , Proteína C-Reactiva , Interleucina-6 , Obesidad , Polimorfismo de Nucleótido Simple , Circunferencia de la Cintura , Adolescente , Biomarcadores/sangre , Proteína C-Reactiva/genética , Proteína C-Reactiva/metabolismo , Niño , Femenino , Humanos , Inflamación/sangre , Inflamación/genética , Inflamación/patología , Interleucina-6/sangre , Interleucina-6/genética , Masculino , Obesidad/sangre , Obesidad/genética , Obesidad/patología , Factores SexualesRESUMEN
PURPOSE: To evaluate the impact of bone metastasis (BM) onset toward prognosis in metastatic renal cell carcinoma (mRCC) patients treated with sunitinib. METHODS: mRCC patients with BM and sunitinib as first targeted therapy between May 2005 and December 2012 were retrospectively analyzed. Patients with synchronous (s) BM or metachronous (m) BM were compared with regard to treatment and outcome [time to clinical progression (TTcP), overall survival (OS), skeletal-related events (SRE)]. Descriptive statistics, Kaplan-Meier estimation of TTcP and OS, Cox regression analyses, and a landmark analysis were administered. RESULTS: BM was identified in 127 mRCC patients; thereof, 82 sunitinib-treated patients were analyzed [sBM n = 57 (69.5 %), mBM n = 25 (30.5 %)]. Higher tumor grading (p = 0.029), male predominance (p = 0.02), and less second-line therapy (p = 0.001) were detected in sBM compared to mBM. SRE remained similar between subgroups (p = 0.462). TTcP during sunitinib was similar [median sBM 8.1 (95 % CI 3.9-12.3) vs. mBM 8.7 (95 % CI 2.7-14.8) months, p = 0.903]. OS remained significantly inferior in sBM patients compared to mBM [median sBM 21.1 (95 % CI 16-26.2) months vs. mBM 38.5 (95 % CI 15-62) months, p = 0.001], which was confirmed by landmark analyses at 1.5, 3, 6, 9, and 12 months. However, OS after occurrence of BM was similar in both groups [median sBM 24.2 (95 % CI 17.3-31.1) months vs. mBM 17.2 (95 % CI 8.4-26) months, p = 0.519]. CONCLUSIONS: mBM is associated with an improved OS compared to sBM in mRCC with sunitinib treatment, despite similar efficacy of sunitinib treatment in both groups of patients.
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Antineoplásicos/uso terapéutico , Neoplasias Óseas/mortalidad , Neoplasias Óseas/secundario , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/mortalidad , Indoles/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Pirroles/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/secundario , Femenino , Humanos , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Sunitinib , Tasa de SupervivenciaRESUMEN
The structural and conformational properties of chloromethyl thiocyanate, CH2ClSCN, were studied in the solid phase and in the gas phase using in situ low-temperature single-crystal X-ray diffraction experiments (XRD) and gas electron diffraction (GED), respectively. Depending on the mutual orientation of the Cl-C bond and the -SCN group, two conformations, gauche and anti, were found to coexist in the gas phase. The gauche conformer, with a dihedral angle φ(ClC-SC) = 71.8(4)°, is the most stable form, with an abundance of 89(3)% at ambient temperature. High level quantum-chemical calculations at the CCSD(T)/cc-pVTZ level of approximation reproduce these experimental results. In the solid state only gauche conformers were found to be present. The crystal structure shows specific intermolecular interactions including chalcogen-type interactions. The experimental electron density distribution was determined by high-angle X-ray diffraction. The atoms in molecules (AIM) theory was applied to analyze the charge density topology for a better characterization of intermolecular interactions present in the crystal.
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To study the prevalence and prognostic importance of mutations in NADH dehydrogenase subunit 4 (ND4), a mitochondrial encoded transmembrane component of the electron transport chain respiratory Complex I, 452 AML patients were examined for ND4 mutations by direct sequencing. The prognostic impact of ND4 mutations was evaluated in the context of other clinical prognostic markers and genetic risk factors. In all, 29 of 452 patients (6.4%) had either somatic (n=12) or germline (n=17) ND4 mutations predicted to affect translation. Somatic mutations were more likely to be heteroplasmic (P<0.001), to occur in predicted transmembrane domains (P<0.001) and were predicted to have damaging effects upon translation (P<0.001). Patients with somatically acquired ND4 mutations had significantly longer relapse-free survival (P=0.017) and overall survival (OS) (P=0.021) than ND4(wildtype) patients. Multivariate analysis also demonstrated a tendency for increased survival in patients with somatic ND4 mutations (RFS: hazard ratio (HR) 0.25, confidence interval (CI) 0.06-1.01, P=0.052; OS: HR 0.29, CI 0.74-1.20, P=0.089). Somatic ND4(mutated) patients had a higher prevalence of concomitant DNMT3A mutations (P=0.023) and a higher percentage of the NPM1/FLT3-ITD low-risk genotype (P=0.021). Germline affected cases showed higher BAALC (P=0.036) and MLL5 (P=0.051) expression levels. Further studies are warranted to validate the favorable prognostic influence of acquired ND4 mutations in AML.
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Biomarcadores de Tumor/genética , Leucemia Mieloide Aguda/genética , Mutación , NADH Deshidrogenasa/genética , Adulto , Secuencia de Bases , Cartilla de ADN , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nucleofosmina , Reacción en Cadena de la Polimerasa , Pronóstico , Factores de RiesgoRESUMEN
OBJECTIVE: To evaluate the clinical efficacy of a new variant of a foam-based negative wound pressure wound therapy (NPWT) system. METHOD: A newly available polyurethane foam-based NPWT system (RENASYS-F, Smith & Nephew) was used to treat 18 patients in a prospective, multi-centre study. The patients had a variety of wound types including pressure ulcers, diabetic foot ulcers, traumatic and surgical wounds. RESULTS: The mean patient age was 48.3 years (range 25-72). Mean treatment duration was 14.6 days (range 5-29). At the end of therapy, 83% (15) wounds had progressed sufficiently, leading to a change in treatment from NPWT. Median reductions in wound area, depth and volume of 31.3%, 45.5% and 74.2% respectively were observed over the course of therapy. This equated to a weekly reduction in area, depth and volume of 12.9%, 20.0% and 32.1% respectively. Exudate level (p = 0.013) and wound malodour (p = 0.03) were significantly reduced between the onset and the end of NPWT. The percentage cover of 'beefy' red granulation tissue in the wound bed was significantly increased (p < 0.001) and non-viable tissue significantly reduced (p = 0.008) between the onset and the end of NPWT. CONCLUSION: These data demonstrate that an alternative foam-based NPWT system (RENASYS-F) is able to address the common treatment goals associated with application of NPWT including reduction in wound dimensions, reduction in exudate levels and an improvement in wound bed quality.
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Terapia de Presión Negativa para Heridas , Cicatrización de Heridas , Tejido de Granulación , Humanos , Estudios Prospectivos , Resultado del Tratamiento , Heridas y LesionesRESUMEN
PURPOSE: The tyrosine kinase inhibitor (TKI) sunitinib induces partial remissions (PR) in a substantial proportion of patients with metastatic renal cell carcinoma (mRCC). Only little is known about the activity of sunitinib in renal lesions in patients with metastatic disease, as most patients with synchronous metastases receive palliative nephrectomy. METHODS: Fourteen patients with clear cell mRCC with renal lesions and sunitinib therapy (50 mg OD, 4/2 scheme) were retrieved retrospectively from clinic records. Tumor assessment consisted of CT scans at least every two cycles, analyzed according to RECIST. In 5 of 14 patients, renal tumors were considered as the primary tumor, while the remaining patients had kidney metastases. In total, 65 target lesions were evaluated. RESULTS: The median progression-free survival (PFS) of sunitinib was 8.7 months (range: 2.7-40.2). Median overall survival (OS) from initiation of TKI therapy was 26 months (range: 3-55). Best response according to RECIST consisted of partial remission (PR) in 4 patients, stable disease (SD) in 7 patients, a complete remission (CR) in 1 patient, and 2 patients with progressive disease (PD). Analyzing the response of renal lesions only, 1 patient had PD, 8 patients had SD, 4 patients had PR, and 1 had a CR. Palliative nephrectomy was performed after two courses of sunitinib in 2 patients. CONCLUSIONS: In our cohort, similar responses of renal tumors and peripheral metastases were achieved with sunitinib treatment. Our results support the use of sunitinib to control renal tumor lesions in metastatic patients.
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Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/secundario , Indoles/uso terapéutico , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/secundario , Pirroles/uso terapéutico , Adulto , Anciano , Carcinoma de Células Renales/cirugía , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Riñón/patología , Riñón/cirugía , Neoplasias Renales/cirugía , Masculino , Persona de Mediana Edad , Nefrectomía , Cuidados Paliativos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Estudios Retrospectivos , Sunitinib , Resultado del TratamientoRESUMEN
Molecularly targeting signaling pathways that are involved in the pathogenesis of hematopoietic malignancies may lead to more specific and efficacious therapies. Activation of the RAS signal transduction cascade is a common feature in the molecular pathogenesis of hematologic malignancies. A number of novel agents targeting RAS signaling have been developed over the past decade. This review will focus on these agents, which include inhibitors of RAS post-translational modification (farnesyl transferase (FTase)-, geranylgeranyl transferase-I (GGTase-I)-, isoprenylcysteine carboxylmethyltransferase (ICMTase)-inhibitors, statins, bisphosphonates), and inhibitors of RAF and MEK activity. Although some of these inhibitors (e.g. FTase, RAF and MEK inhibitors) were developed to specifically inhibit RAS signaling, it has become clear that RAS may not be the only critical target of these compounds. This review provides a background on RAS signaling in hematologic malignancies and discusses opportunities to exploit aberrant cancer cell signaling in order to develop better treatment options for patients suffering from these diseases.
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GTP Fosfohidrolasas/antagonistas & inhibidores , Enfermedades Hematológicas/metabolismo , Transducción de Señal , Inhibidores Enzimáticos/farmacología , GTP Fosfohidrolasas/metabolismo , HumanosRESUMEN
Despite significant advances in the use of surgery, chemotherapy and radiotherapy to treat squamous cell carcinoma of the head and neck (SCCHN), prognosis has improved little over the past 30 years. There is a clear need for novel, more effective therapies to prevent relapse, control metastases and improve overall survival. Improved understanding of SCCHN disease biology has led to the introduction of molecularly targeted treatment strategies in these cancers. The epidermal growth factor receptor (EGFR) is expressed at much higher levels in SCCHN tumours than in normal epithelial tissue, and EGFR expression correlates with poor prognosis. Therefore, much effort is currently directed toward targeting aberrant EGFR activity (e.g. cell signalling) in SCCHN. This review discusses the efficacy of novel therapies targeting the EGFR (e.g. anti-EGFR antibodies and EGFR tyrosine kinase inhibitors) that are currently tested in SCCHN patients.
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Antineoplásicos/uso terapéutico , Carcinoma de Células Escamosas/tratamiento farmacológico , Receptores ErbB/antagonistas & inhibidores , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Transducción de Señal/efectos de los fármacos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Cetuximab , Terapia Combinada , Receptores ErbB/genética , Receptores ErbB/fisiología , Gefitinib , Humanos , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/uso terapéuticoRESUMEN
Numerous treatment concepts for advanced but resectable oral and oropharyngeal squamous cell carcinoma exist. In this study, we present the 7-year results of a promising treatment with preoperative simultaneous chemoradiation using paclitaxel and carboplatin within a prospective phase II trial comprising 56 patients. After determination of the local tumor extension, chemoradiation was applied for 4 weeks and up to 40 Gy. Following a recovery period of 3-4 weeks, tumor resection was performed within the initially tattooed resection margins, together with a functional modified neck dissection. The median follow-up time was 44.9 +/- 19.6 months (range 0.76-87.9). After 7 years, 35 (63.3%) patients were alive and 20 (36.4%) had died. In 2 patients (3.6%), the cause of death was related to treatment. After 7 years, the overall survival rate declined to 63.6%, whereas the local recurrence-free probability was still 84.2%. These results confirm the excellent local control and high survival rates of preoperative radiochemotherapy with the combination of paclitaxel/carboplatin.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/radioterapia , Neoplasias Orofaríngeas/tratamiento farmacológico , Neoplasias Orofaríngeas/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Carboplatino/administración & dosificación , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/radioterapia , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Boca/patología , Estadificación de Neoplasias , Neoplasias Orofaríngeas/patología , Paclitaxel/administración & dosificación , Cuidados Preoperatorios , Pronóstico , Estudios Prospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: In oxygen-enhanced lung MRI, difference maps of acquisitions during inhalation of room air and pure oxygen are calculated to assess lung function. The purpose of this study was to analyze how the calculation of these difference maps depends on the delayed signal change after switching the gas supply. METHODS: Ten healthy volunteers were examined with an ECG and respiratory-triggered T1-weighting inversion recovery HASTE sequence with parallel imaging. Four blocks with 20 repetitions of up to 6 coronal slices were continuously acquired; in blocks 1 and 3 room air was supplied, in blocks 2 and 4 oxygen. Data were postprocessed, discarding between 0 and 19 repetitions after each change of gas supply before calculating the relative signal difference. RESULTS: The averaged relative signal difference increases from 9.4 to 17.4% when the number of discarded acquisitions increases; the ratio of signal difference and spatial standard deviation reaches a maximum at 5-8 discarded acquisitions. CONCLUSIONS: An optimized ratio of signal difference and statistical error is found if about 5-8 of 20 respiratory-triggered repetitions are discarded after each change of gas supply for the calculation of difference maps.
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Aumento de la Imagen/métodos , Interpretación de Imagen Asistida por Computador/métodos , Imagenología Tridimensional/métodos , Pulmón/anatomía & histología , Imagen por Resonancia Magnética/métodos , Oxígeno , Técnica de Sustracción , Adulto , Medios de Contraste/administración & dosificación , Femenino , Humanos , Masculino , Oxígeno/administración & dosificación , Reproducibilidad de los Resultados , Mecánica Respiratoria , Sensibilidad y EspecificidadRESUMEN
The direction, intensity and shape of viability-, sexual- and fecundity selection on body mass were investigated in a natural population of the greater white-toothed shrew (Crocidura russula), combining parentage assignment through molecular techniques and mark-recapture data over several generations. A highly significant stabilizing viability selection was found in both sexes, presumably stemming from the constraints imposed by their insectivorous habits and high metabolic costs. Sexual selection, directional in both sexes, was twice as large in males than in females. Our results suggest that body mass matters in this context by facilitating the acquisition and defense of a breeding territory. No fecundity selection could be detected. The direction of sexual size dimorphism (SSD) was in agreement with the observed pattern of selective pressures: males were heavier than females, because of stronger sexual selection. SSD intensity, however, was low compared with other mammals, because of the low level of polygyny, the active role of females in territory defense and the intensity of stabilizing viability selection.
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Peso Corporal/fisiología , Fertilidad/fisiología , Selección Genética , Caracteres Sexuales , Musarañas/fisiología , Animales , Femenino , Genotipo , Masculino , Repeticiones de Microsatélite/genética , Linaje , Factores Sexuales , Conducta Sexual Animal/fisiología , Musarañas/genética , Suiza , TerritorialidadRESUMEN
Farnesyltransferase inhibitors (FTIs) represent a new class of anticancer agents that specifically target post-translational farnesylation of various proteins that mediate several cellular processes such as signal transduction, growth, differentiation, angiogenesis and apoptosis. These compounds were originally designed to block oncogenic RAS-induced tumor growth by impeding RAS localization to the membrane, but it is now evident that FTIs also affect processing of several other proteins. The need for novel therapies in myeloid leukemia is underscored by the high rate of treatment failure due to high incidences of relapse- and treatment-related toxicities. As RAS deregulation is important in the pathogenesis of myeloid leukemias, targeting of RAS signaling may provide a new therapeutic strategy. Several FTIs (eg BMS-214662, L-778,123, R-115777 and SCH66336) have entered phase I and phase II clinical trials in myeloid leukemias. This review discusses recent clinical results, potential combination therapies, mechanisms of resistance and the clinical challenges of toxicities associated with prenylation inhibitors.
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Antineoplásicos/farmacología , Leucemia Mieloide/tratamiento farmacológico , Prenilación de Proteína/efectos de los fármacos , Transferasas Alquil y Aril/antagonistas & inhibidores , Antineoplásicos/química , Resistencia a Antineoplásicos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Farnesiltransferasa , Humanos , Resultado del Tratamiento , Proteínas ras/metabolismoRESUMEN
As deregulation of RAS signaling is important in the pathogenesis of myeloid leukemias, molecular targeting of RAS signaling may be a promising therapeutic strategy. Farnesyl transferase inhibitors (FTIs) are the most promising class of these new cancer therapeutics. Several FTIs have entered phase II clinical trials in acute myeloid leukemia (AML). Since geranylgeranylation of K-RAS and N-RAS in the presence of FTIs may represent an important mechanism of FTI resistance, 6 geranylgeranyl transferase-I inhibitors (GGTIs) were screened alone and in combination with FTI for growth inhibition of myeloid leukemia cells. Significant growth inhibition (>70%) in myeloid cell lines was observed for GGTI-286 (9/19), GGTI-298 (14/19), GGTI-2147 (16/19) and FTI L-744,832 (17/17). GGTI treatment of NB-4 cells resulted in an accumulation of cells in G(0)/G(1), whereas FTI L-744,832 primarily caused an increase in G(2)/M. FTI and GGTIs both induced apoptosis. In all cases, FTI/GGTI cotreatment led to synergistic cytotoxic effects in both myeloid cell lines (5/5) and primary AML cells (6/6). This synergy coincided with increased apoptosis. FTI/GGTI cotreatment caused an accumulation of unprocessed N-RAS and inactive N-RAS-RAF complexes. Our results suggest that alternative geranylgeranylation of N-RAS may represent an important mechanism of resistance to FTI monotherapy in myeloid leukemia cells.
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Transferasas Alquil y Aril/antagonistas & inhibidores , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Apoptosis/efectos de los fármacos , Leucemia Mieloide/patología , Adulto , División Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Sinergismo Farmacológico , Inhibidores Enzimáticos/farmacología , Farnesiltransferasa , Citometría de Flujo , Humanos , Interfase/efectos de los fármacos , Células Tumorales Cultivadas , Proteínas ras/efectos de los fármacos , Proteínas ras/metabolismoRESUMEN
A new type of [1]rotaxanes containing two aliphatic bridges between axle and wheel is obtained in 39% yield in a one-step synthesis starting from a [2]rotaxane which contained one sulfonamide group each in both the wheel and the axle. Temperature controlled chemoselective substitution reactions first at these sulfonamide nitrogens and then subsequently at the various other carboxamide nitrogens in the wheel and axle give rise to the formation of an isomeric mixture of three double-bridged [1]rotaxanes which could be separated by HPLC. Structure determination of the main product 3a was possible by NMR experiments supported by molecular modeling calculations. Using different reaction conditions, a double-substituted but not yet bridged [2]rotaxane 4 could be isolated as an intermediate giving further evidence for the assigned structure of 3a and the way of its formation. The shape of this double-bridged [1]rotaxane 3a reminds of a self-intertwining chiral "molecular 8", in which any possible racemization due to deslipping is hindered by the two stoppers originating from the former rotaxane axle. Hence, to the best of our knowledge this is the first example of a molecule in which both concepts, cycloenantiomerism and helical chirality, are realised in one structure. Enantiomer separation of the main product was possible by further HPLC using chiral stationary phases. The Cotton effects of the circular dichrograms are different to those of the already synthesized [1]rotaxanes bearing just one aliphatic bridge between axle and wheel.
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Disruption of the RAS-to-mitogen-activated protein kinase (MAPK/ERK) signaling pathway, either directly through activating RAS gene mutations or indirectly through other genetic aberrations, plays an important role in the molecular pathogenesis of myeloid leukemias. Constitutive activation of ERK-1/2 and MEK-1/2, which elicit oncogenic transformation in fibroblasts, has recently been observed in acute myeloid leukemias (AML). In this study, the activation of the RAS-to-MAPK cascade in 14 AML and 5 chronic myeloid leukemia (CML) cell lines is examined and correlated with the effects of a panel of 9 RAS signaling inhibitors on cell viability, colony formation, cell-cycle progression, and induction of apoptosis. Activation of MEK, ERK, and the transcription factors CREB-1, ATF-1, and c-Myc is demonstrated in the majority of the cell lines (9 of 14 AML and 2 of 5 CML cell lines). Although activation of the ERK cascade did not always correlate with the presence of activating RAS mutations or BCR-Abl, it is linked to the G0/G1 and the G2/M phase of the cell cycle. In contrast to most inhibitors (eg, B581, Cys-4-Abs-Met, FPT-2, FTI-276, and FTS), a significant growth inhibition was only observed for FTI-277 (19 of 19), FPT-3 (10 of 19), and the MEK inhibitors U0126 (19 of 19) and PD098059 (8 of 19). Treatment of NB-4 cells with FTI-277 primarily resulted in a G2/M block, whereas treatment with FPT-3 and U0126 led to induction of apoptosis. FTI-277 revealed strong toxicity toward normal purified CD34+ cells. The results suggest differences in the mechanisms of action and support a potential therapeutic usefulness of these inhibitors in the treatment of myeloid leukemias.
Asunto(s)
Ciclo Celular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Leucemia Mieloide/tratamiento farmacológico , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Apoptosis/efectos de los fármacos , Ciclo Celular/fisiología , División Celular/efectos de los fármacos , Análisis Mutacional de ADN , Activación Enzimática , Humanos , Leucemia Mieloide/enzimología , Leucemia Mieloide/patología , MAP Quinasa Quinasa 1 , MAP Quinasa Quinasa 2 , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Quinasas de Proteína Quinasa Activadas por Mitógenos/fisiología , Mutación , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/fisiología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Proteínas Tirosina Quinasas/fisiología , Transducción de Señal/efectos de los fármacos , Células Madre/efectos de los fármacos , Factores de Transcripción/metabolismo , Células Tumorales Cultivadas , Proteínas ras/antagonistas & inhibidores , Proteínas ras/genética , Proteínas ras/metabolismoRESUMEN
A series of alterations in the cellular genome affecting the expression or function of genes controlling cell growth and differentiation is considered to be the main cause of cancer. These mutational events include activation of oncogenes and inactivation of tumor suppressor genes. The elucidation of human cancer at the molecular level allows the design of rational, mechanism-based therapeutic agents that antagonize the specific activity of biochemical processes that are essential to the malignant phenotype of cancer cells. Because the frequency of RAS mutations is among the highest for any gene in human cancers, development of inhibitors of the Ras-mitogen-activated protein kinase pathway as potential anticancer agents is a very promising pharmacologic strategy. Inhibitors of Ras signaling have been shown to revert Ras-dependent transformation and cause regression of Ras-dependent tumors in animal models. The most promising new class of these potential cancer therapeutics are the farnesyltransferase inhibitors. The development of these compounds has been driven by the observation that oncogenic Ras function is dependent upon posttranslational modification, which enables membrane binding. In contrast to many conventional chemotherapeutics, farnesyltransferase inhibitors are remarkably specific and have been demonstrated to cause no gross systemic toxicity in animals. Some orally bioavailable inhibitors are presently being evaluated in phase II clinical trials. This review presents an overview on some inhibitors of the Ras signaling pathway, including their specificity and effectiveness in vivo. Because Ras signaling plays a crucial role in the pathogenesis of some hematologic malignancies, the potential therapeutic usefulness of these inhibitors is discussed. (Blood. 2000;96:1655-1669)