RESUMEN
A stable preparation of agaricinic acid nanoparticles was obtained. The mean hydrodynamic size of nanoparticles according to photon correlation spectroscopy was 200 nm and zeta potential was -57 mV. Cytotoxic activity of agaricinic acid nanoparticles against human HepG2 hepatoma cells was evaluated. Nanoparticles with a low concentration of agaricinic acid stimulated and with high concentration - suppressed metabolic activity and viability of hepatoma cells. The EC50 for the stimulating effect was 32.8 µg/ml, and the IC50=602.1 mg/ml. The preparation of agaricinic acid nanoparticles can be used in medicine as a potential antitumor agent.
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Alcanos/farmacología , Antineoplásicos/farmacología , Coriolaceae/química , Nanopartículas/química , Ácidos Tricarboxílicos/farmacología , Alcanos/aislamiento & purificación , Antineoplásicos/aislamiento & purificación , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Cuerpos Fructíferos de los Hongos/química , Células Hep G2 , Humanos , Tamaño de la Partícula , Ácidos Tricarboxílicos/aislamiento & purificaciónRESUMEN
Over the last decade, a dual character of cell response to oxidative stress, eustress versus distress, has become increasingly recognized. A growing body of evidence indicates that under physiological conditions, low concentrations of reactive oxygen and nitrogen species (RONS) maintained by the activity of endogenous antioxidant system (AOS) allow reversible oxidative/nitrosative modifications of key redox-sensitive residues in regulatory proteins. The reversibility of redox modifications such as Cys S-sulphenylation/S-glutathionylation/S-nitrosylation/S-persulphidation and disulphide bond formation, or Tyr nitration, which occur through electrophilic attack of RONS to nucleophilic groups in amino acid residues provides redox switches in the activities of signalling proteins. Key requirement for the involvement of the redox modifications in RONS signalling including ROS-MAPK, ROS-PI3K/Akt, and RNS-TNF-α/NF-kB signalling is their specificity provided by a residue microenvironment and reaction kinetics. Glutathione, glutathione peroxidases, peroxiredoxins, thioredoxin, glutathione reductases, and glutaredoxins modulate RONS level and cell signalling, while some of the modulators (glutathione, glutathione peroxidases and peroxiredoxins) are themselves targets for redox modifications. Additionally, gene expression, activities of transcription factors, and epigenetic pathways are also under redox regulation. The present review focuses on RONS sources (NADPH-oxidases, mitochondrial electron-transportation chain (ETC), nitric oxide synthase (NOS), etc.), and their cross-talks, which influence reversible redox modifications of proteins as physiological phenomenon attained by living cells during the evolution to control cell signalling in the oxygen-enriched environment. We discussed recent advances in investigation of mechanisms of protein redox modifications and adaptive redox switches such as MAPK/PI3K/PTEN, Nrf2/Keap1, and NF-κB/IκB, powerful regulators of numerous physiological processes, also implicated in various diseases.
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Proteínas Quinasas Activadas por Mitógenos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Procesamiento Proteico-Postraduccional , Especies de Nitrógeno Reactivo/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Glutatión Peroxidasa/metabolismo , Humanos , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Nitrosación , Oxidación-Reducción , Fosfohidrolasa PTEN/metabolismo , Peroxirredoxinas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Tiorredoxinas/metabolismoRESUMEN
BACKGROUND: Gastroesophageal reflux (GER) has been associated with idiopathic pulmonary fibrosis (IPF). Pathogenesis may be related to chronic micro-aspiration. We aimed to assess objective measures of GER on multichannel intraluminal impedance and pH study (MII-pH) and their relationship with pulmonary function testing (PFT) results, and to compare the performance of pH/acid reflux parameters vs corresponding MII/bolus parameters in predicting pulmonary dysfunction in IPF. METHODS: This was a retrospective cohort study of IPF patients undergoing prelung transplant evaluation with MII-pH off acid suppression, and having received PFT within 3 months. Patients with prior fundoplication were excluded. Severe pulmonary dysfunction was defined using diffusion capacity of the lung for carbon monoxide (DLCO) ≤40%. Six pH/acid reflux parameters with corresponding MII/bolus reflux measures were specified a priori. Multivariate analyses were applied using forward stepwise logistic regression. Predictive value of each parameter for severe pulmonary dysfunction was calculated by area-under-the-receiver-operating-characteristic-curve or c-statistic. KEY RESULTS: Forty-five subjects (67% M, age 59, 15 mild-moderate vs 30 severe) met criteria for inclusion. Patient demographics and clinical characteristics were similar between pulmonary dysfunction groups. Abnormal total reflux episodes and prolonged bolus clearance time were significantly associated with pulmonary dysfunction severity on univariate and multivariate analyses. No pH parameters were significant. The c-statistic of each pH parameter was lower than its MII counterpart in predicting pulmonary dysfunction. CONCLUSIONS & INFERENCES: MII/bolus reflux, but not pH/acid reflux, was associated with pulmonary dysfunction in prelung transplant patients with IPF. MII-pH may be more valuable than pH testing alone in characterizing GER in IPF.
Asunto(s)
Monitorización del pH Esofágico/métodos , Reflujo Gastroesofágico/diagnóstico , Fibrosis Pulmonar Idiopática/diagnóstico , Enfermedades Pulmonares/diagnóstico , Impedancia Eléctrica , Femenino , Reflujo Gastroesofágico/complicaciones , Humanos , Concentración de Iones de Hidrógeno , Fibrosis Pulmonar Idiopática/complicaciones , Enfermedades Pulmonares/complicaciones , Masculino , Persona de Mediana Edad , Curva ROC , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Gastroesophageal reflux disease has been associated with poor outcomes following lung transplantation. However, the association between pretransplant reflux and post-transplant readmission, an indicator of early clinical outcome, has not been previously assessed. METHODS: This was a retrospective cohort study of lung transplant recipients undergoing pretransplant multichannel intraluminal impedance and pH (MII-pH) study off acid suppression at a tertiary care center since 2007. Subjects with pretransplant fundoplication were excluded. Time to readmission was defined as duration from post-transplant discharge to next hospital admission for any reason. Subgroup analysis was performed to exclude elective readmissions. Time-to-event analysis was performed using Cox proportional hazards model, with appropriate censoring. KEY RESULTS: Forty-three subjects (60% men, mean age: 57, median follow-up: 1.7 years) met inclusion criteria for the study. Patient demographics and pretransplant cardiopulmonary function were similar between readmission cohorts. Time to all-cause readmission was associated with increased distal acid episodes (HR: 3.15, p = 0.04) and proximal acid episodes (HR: 3.61, p = 0.008) on impedance, increased acid exposure on pH (HR: 2.22, p = 0.04), and elevated Demeester score (HR: 2.26, p = 0.03). When elective readmissions were excluded, early readmission remained significantly associated with increased proximal acid reflux episodes (HR: 2.49, p = 0.04). All findings were confirmed on Kaplan-Meier analysis. CONCLUSIONS & INFERENCES: Elevated proximal acid reflux on pretransplant MII-pH testing was associated with early readmission following lung transplantation, even after excluding elective readmissions. Exposure to severe acid reflux has measurable effects on early postoperative outcomes such as readmission, and aggressive early antireflux therapy should be considered.
Asunto(s)
Reflujo Gastroesofágico/complicaciones , Trasplante de Pulmón , Readmisión del Paciente/estadística & datos numéricos , Adulto , Estudios de Cohortes , Impedancia Eléctrica , Monitorización del pH Esofágico , Femenino , Humanos , Concentración de Iones de Hidrógeno , Estimación de Kaplan-Meier , Trasplante de Pulmón/mortalidad , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios RetrospectivosRESUMEN
OBJECTIVE: To evaluate the distribution of first- and second-trimester maternal serum markers in twin pregnancy with and without pre-eclampsia. METHODS: One-hundred and forty-four twin and 109 unaffected singleton pregnancies were recruited from the same institution. First- and second-trimester maternal blood samples were stored and measured retrospectively for serum placental growth factor (PlGF), pregnancy-associated plasma protein-A (PAPP-A), free ß-human chorionic gonadotropin (ß-hCG) and α-fetoprotein (AFP). All had measurement of first-trimester serum markers, and 167 (66%) had second-trimester tests. Values were expressed in multiples of the gestation-specific median (MoMs) in singletons, adjusted for maternal weight, as appropriate. RESULTS: Pre-eclampsia was diagnosed in 12 (9.0%) twin pregnancies of 133 continuing beyond 22 weeks. In unaffected twin pregnancies, all serum markers were statistically significantly increased (P < 0.0001), consistent with a doubling of concentration. Among twin pregnancies, those with pre-eclampsia had a significantly reduced median PlGF compared with surviving unaffected twin pregnancies (0.96 MoM vs 1.46 MoM; P < 0.0002, two-tailed), whilst median PAPP-A, which is known to be reduced in affected singleton pregnancies, was increased (3.91 MoM vs 2.43 MoM; P < 0.0005, two-tailed). The levels of free ß-hCG (P < 0.02) and AFP (P < 0.05) were also significantly raised, but to a lesser extent than was the level of PAPP-A. Using a logistic regression algorithm based on first- and second-trimester PlGF and PAPP-A, together with previously published uterine artery Doppler and mean arterial pressure measurements in the same series, the predicted pre-eclampsia detection rate was 65% for a 10% false-positive rate. CONCLUSIONS: In twin pregnancy, the predicted detection rate of pre-eclampsia using first- and second-trimester maternal serum and biophysical markers is good. In contrast to singleton pregnancy, PAPP-A levels are raised in the first trimester of twin pregnancies destined to develop pre-eclampsia and therefore a different prediction algorithm is needed. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.
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Biomarcadores/sangre , Preeclampsia/diagnóstico , Embarazo Gemelar/sangre , Adulto , Gonadotropina Coriónica Humana de Subunidad beta/sangre , Femenino , Humanos , Factor de Crecimiento Placentario/sangre , Preeclampsia/metabolismo , Embarazo , Primer Trimestre del Embarazo/sangre , Segundo Trimestre del Embarazo/sangre , Proteína Plasmática A Asociada al Embarazo/metabolismo , Sensibilidad y Especificidad , alfa-Fetoproteínas/metabolismoRESUMEN
BACKGROUND: Gastroesophageal reflux (GER) has been associated with idiopathic pulmonary fibrosis (IPF), although the mechanism remains unclear. Gastroesophageal reflux/microaspiration may lead to lung fibrosis, while increased pulmonary workload may also worsen GER. Comparing the GER profile of IPF patients to chronic obstructive pulmonary disease (COPD) patients with similar lung function may help delineate the role of GER in IPF pathogenesis. METHODS: This was a retrospective cohort study of IPF and COPD patients undergoing pre-lung transplant multichannel intraluminal impedance and pH study (MII-pH) off acid suppression at a tertiary center in 2008-2014. Patients with prior fundoplication were excluded. Baseline demographics, pulmonary function test, and MII-pH results were recorded. Univariate analyses were performed using Fisher's exact (binary variables) and Student's t (continuous variables) tests. Logistic regression was performed to adjust for potential confounders. KEY RESULTS: A total of 90 subjects (54 IPF, 36 COPD) met inclusion criteria. Compared to COPD, IPF patients had increased total reflux episodes (65.9 vs 46.1, p = 0.02), proximal reflux episodes (30.3 vs 20.3, p = 0.04), and prevalence of abnormal total reflux episodes (38.9% vs 16.7%, p = 0.02). On multivariate analyses, abnormal total reflux episodes (OR: 4.9, p = 0.05) and bolus reflux exposure time (OR: 4, p = 0.04) remained significantly associated with IPF. CONCLUSIONS & INFERENCES: Abnormal reflux was significantly more prevalent among IPF patients after controlling for lung disease severity. Gastroesophageal reflux/microaspiration likely plays a role in fibrosis in IPF. A significant portion of IPF patients had increased non-acid reflux. Therapies aiming to prevent reflux of gastric contents may be more beneficial than antisecretory medications alone in these patients.
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Reflujo Gastroesofágico/diagnóstico , Fibrosis Pulmonar Idiopática/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Estudios de Cohortes , Impedancia Eléctrica , Monitorización del pH Esofágico , Femenino , Reflujo Gastroesofágico/fisiopatología , Humanos , Fibrosis Pulmonar Idiopática/fisiopatología , Trasplante de Pulmón , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Estudios RetrospectivosRESUMEN
The natural history of KPC-producing Klebsiella pneumoniae (KPC KP) carriage is unknown. We aimed to examine the duration of KPC KP carriage following hospital discharge and to study the risk factors for persistent carriage. A cohort of 125 KPC KP carriers was followed monthly for between 3 and 6 months after discharge from an acute-care hospital. Rectal swabs and data were collected at baseline and at each visit. KPC KP was detected by culture and direct blaKPC PCR. Acquisition time was regarded as the earliest date of KPC KP isolation. Resolution of carriage was defined as a negative KPC KP test in at least two consecutive samples. Analyses were separated for recent (<4 months) (REC, 75 patients) and remote (≥4 months) (REM, 50 patients) acquisition groups. Risk factors for persistent carriage were examined by survival analyses for the REC group and by prevalence methods for the REM group. The mean age of patients was 67.5 years and 49.6% were male. Forty-six (61%) patients in the REC group and 14 (28%) in the REM group were persistent carriers (p < 0.001). A significant risk factor for persistent carriage identified in both the REC and REM groups was the presence of any catheter (p < 0.05). Unique risk factor groups included long-term care facility (LTCF) residence (p < 0.01) and a low functional status as measured by the Barthel's index (p < 0.05) in the REC group and high Charlson's score in the REM group (p < 0.05). Out of the entire 100 patients who had at least one negative sample, only 65 remained negative on subsequent cultures. In conclusion, persistent carriage of KPC KP is associated with catheter use and a low functional status; it is more common in patients with recent acquisition and is related to LTCF stay. A single negative KPC KP test is insufficient to exclude persistent carriage.
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Portador Sano/epidemiología , Tracto Gastrointestinal/microbiología , Infecciones por Klebsiella/epidemiología , Klebsiella pneumoniae/enzimología , beta-Lactamasas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Portador Sano/microbiología , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Hospitales , Humanos , Infecciones por Klebsiella/microbiología , Klebsiella pneumoniae/aislamiento & purificación , Masculino , Persona de Mediana Edad , Alta del Paciente , Estudios Prospectivos , Factores de Riesgo , Factores de TiempoRESUMEN
INTRODUCTION: Leprosy is a regional problem of public health in the Argentine Republic. It has seen a continuous decrease of the prevalence in the last 10 years, with value is about 0.17/10000 citizen and the detection rate is constant about 0.10/10000 citizen. Even the death rate is low, its importance is given for the physicals, socials, permanents and the progressive disabilities that its produce if there no early diagnostic and a regular and complete treatment. The Dr. Baldomero Sommer National Hospital, that give a complete assistance to the leprosy patients either to the pavilion patients or the ill patients that help oneselves and live in houses with their families and where it is given food assistance to promote and increase their quality of life. OBJECTIVES: Evaluate The nutritional state of the ill patients that help oneselves and live in houses with their families. Analyze the caloric and proteic brought by the institution. MATERIAL AND METHODS: It is a transversal and descriptive study. We made a nutritional evaluation of the patients that live in each of the 4 suburb of the hospital, whom has been previously appointed by the coordinator of the zone, with the porpoise of identify the nutritional state of each one of the patients, quantify the nutritional risk, and indicate, adequate and monitories the nutritional support. The diagnostic was realized by the dietician through: anthropometric parameters (weight, height and body mass index), biochemical parameters, according to the clinical history: albumin, cholesterol, urea, hematocrito and associated illness. RESULTS: We evaluated 219 patients of 246, with a middle age of 56.4 years, 62.2% males and 57.8% females. We detected that obesity was the nutritional disorder with mayor prevalence in these population (74.3%) and with mayor incidence in the moderate obesity in males and mayor incidence in severe obesity in females. The prevalence of malnourishment was 3.6% and well-nourished was 23.7%, 27 of the patients (10.9%) did not go to the nutritional evaluation. The 2.8% of the patients did not have an actual laboratory for more than 2 years. In the clinical histories, we found that the dosage of albumin in an average of 4.2 g/dl, and the 2.8% of the patients did not have any value of albumin. The values of hematocrito and urea determinate an adequate brought of proteins in the evaluated population. Inside the nutritional diagnostic we considerate the search of diabetes (present ion the 9.7% of the patients), dislipemia (present ion the 32.8% of the patients, taken a level of 200 mg / dl of cholesterol), chronic renal deficiency (present in the 9.3% of the patients), and arterial hypertension (present in the 33.6% of the patients). CONCLUSIONS: Exist a high prevalence of moderate-severe obesity in the studied population that have no coincidence with the universal literature. These data shows the necessity to adequate the caloric and proteic brought to the patients. The majority of the patients presented Dislipemia and or diabetes and or arterial hypertension. Promote the development of educational programs to better the nutritional state of the risk population, better the quality of life and reduce cardiovascular risks, using an international model that include strategies for the following of a health diet and an increase of physical activity.
Asunto(s)
Proteínas en la Dieta , Ingestión de Energía , Servicio de Alimentación en Hospital/normas , Hospitalización , Lepra , Evaluación Nutricional , Argentina , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Introducción: En la República Argentina la Lepra es un problema de salud pública regional. Se observa un continuo descenso de la tasa de prevalencia en los últimos 10 años. El hospital Nac. Dr. Baldomero Sommer brinda asistencia integral al enfermo de Lepra en las modalidades de atención de los pacientes en pabellones y salas de internación en casas que habitan enfermos autoválidos y sus familiares, donde se les provee asistencia alimentaria . Objetivos: Evaluar el estado nutricional de pacientes que residen en el hospital. Analizar el aporte calóricoproteico brindado por la Institución. Material y métodos: Estudio Transversal y Descriptivo. Se realizó una Evaluación Nutricional a los pacientes que residen en los 4 barrios que se encuentran en el hospital. Se obtuvo información disponible en las historias clínicas sobre Parámetros Bioquímicos y de las patologías asociadas prevalentes. Resultados: Se evaluaron 219 pacientes, de un total de 246, edad promedio 56,4 años, 62,2% Hombres y 37,8% Mujeres. La Obesidad resultó el trastorno nutricional de mayor prevalencia (74,3%). Desnutrición 3,6%, Eunutridos 23,7%. No concurrieron a la evaluación 10,9% de los pacientes y 2,8% no tenían laboratorio actualizado (+ de 2 años). El promedio Albúmina fue 4,2 g/dl, 28,45% no tenían registrado valor de Albúmina. Los valores de Hto, Urea determinaron un adecuado aporte proteico. Dentro del diagnóstico nutricional se tuvo en consideración la búsqueda de patologías prevalentes como Diabetes que estuvo presente en el 9,7% de los pacientes, Dislipidemia = 32,8%, IRC = 9,3%, HTA = 33,6%. Conclusiones: Existe una alta prevalencia de Obesidad Moderada-Severa en la población estudiada que no es coincidente con la literatura actual y pone de manifiesto la necesidad de adecuar a la brevedad el aporte calórico-proteico. Impulsar medidas preventivas a través de Programas de Educación con el propósito de mejorar el estado nutricional de la población en riesgo, mejorar la calidad de vida, reducir los factores de riesgo cardiovasculares, utilizando un modelo de intervención que incluya estrategias para el seguimiento de una dieta saludable y el aumento de la actividad física
Introduction: Leprosy is a regional problem of public health in the Argentine Republic. It has seen a continuous decrease of the prevalence in the last 10 years, with value is about 0.17/10000 citizen and the detection rate is constant about 0.10/10000 citizen. Even the death rate is low, its importance is given for the physicals, socials, permanents and the progressive disabilities that its produce if there no early diagnostic and a regular and complete treatment. The Dr. Baldomero Sommer National Hospital, that give a complete assistance to the leprosy patients either to the pavilion patients or the ill patients that help oneselves and live in houses with their families and where it is given food assistance to promote and increase their quality of life. Objectives: Evaluate The nutritional state of the ill patients that help oneselves and live in houses with their families. Analyze the caloric and proteic brought by the institution. Material and methods: It is a transversal and descriptive study. We made a nutritional evaluation of the patients that live in each of the 4 suburb of the hospital, whom has been previously appointed by the coordinator of the zone, with the porpoise of identify the nutritional state of each one of the patients, quantify the nutritional risk, and indicate, adequate and monitories the nutritional support. The diagnostic was realized by the dietician through: anthropometric parameters (weight, height and body mass index), biochemical parameters, according to the clinical history: albumin, cholesterol, urea, hematocrito and associated illness. Results: We evaluated 219 patients of 246, with a middle age of 56.4 years, 62.2% males and 57.8% females. We detected that obesity was the nutritional disorder with mayor prevalence in these population (74.3%) and with mayor incidence in the moderate obesity in males and mayor incidence in severe obesity in females. The prevalence of malnourishment was 3.6% and well-nourished was 23.7%, 27 of the patients (10.9%) did not go to the nutritional evaluation. The 2.8% of the patients did not have an actual laboratory for more than 2 years. In the clinical histories, we found that the dosage of albumin in an average of 4.2 g/dl, and the 2.8% of the patients did not have any value of albumin. The values of hematocrito and urea determinate an adequate brought of proteins in the evaluated population. Inside the nutritional diagnostic we considerate the search of diabetes (present ion the 9.7% of the patients), dislipemia (present ion the 32.8% of the patients, taken a level of 200 mg / dl of cholesterol), chronic renal deficiency (present in the 9.3% of the patients), and arterial hypertension (present in the 33.6% of the patients). Conclusions: Exist a high prevalence of moderate-severe obesity in the studied population that have no coincidence with the universal literature. These data shows the necessity to adequate the caloric and proteic brought to the patients. The majority of the patients presented Dislipemia and or diabetes and or arterial hypertension. Promote the development of educational programs to better the nutritional state of the risk population, better the quality of life and reduce cardiovascular risks, using an international model that include strategies for the following of a health diet and an increase of physical activity
Asunto(s)
Masculino , Femenino , Humanos , Lepra/complicaciones , Trastornos Nutricionales/epidemiología , Evaluación Nutricional , Argentina/epidemiología , Hospitalización/estadística & datos numéricos , Albúmina Sérica/análisis , Factores de Riesgo , Enfermedades Cardiovasculares/epidemiología , Epidemiología DescriptivaRESUMEN
Endogenous inhibitors of angiogenesis are proved to be a major factor preventing the emergence of clinically manifested stages of human cancer. The protein endostatin, a 20-kD proteolytic fragment of type XVIII collagen, is one of the most active natural inhibitors of angiogenesis. Endostatin specifically inhibits the in vitro and in vivo proliferation of endothelial cells, inducing their apoptosis through inhibition of cyclin D1. On the surface of endothelial cells, endostatin binds with the integrin alpha(5)beta(1) that activates the Src-kinase pathway. The binding of endostatin with integrins also down-regulates the activity of RhoA GTPase and inhibits signaling pathways mediated by small kinases of the Ras and Raf families. All these events promote disassembly of the actin cytoskeleton, disorders in cell-matrix interactions, and decrease in endotheliocyte mobility, i.e., promote the suppression of angiogenesis. Endostatin displays a high antitumor activity in vivo: it inhibits the progression of more than 60 types of tumors. This review summarizes results of numerous studies concerning the biological activity and action mechanism of endostatin.
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Endostatinas/fisiología , Neovascularización Patológica/fisiopatología , Animales , Ciclina D1/metabolismo , Endostatinas/metabolismo , Humanos , Integrinas/metabolismo , Neoplasias/irrigación sanguínea , Neoplasias/metabolismo , Neoplasias/patología , Unión Proteica , Transducción de Señal , Proteína de Unión al GTP rhoA/metabolismoRESUMEN
Recently it has been found that the presence of homozygous arginine polymorphism at codon 72 of p53, represents a significant risk factor in the development of HPV-associated cervical cancer. The incidence of cervical carcinoma is persistently very low in Israeli Jewish women for unknown reasons. The incidence among those of North African origin is relatively higher. The aim of the present study was to assess the frequency distribution of the p53 homozygous arginine polymorphism in cervical cancer patients and in a population sample of healthy Israeli Jewish women in order to determine whether the incidence pattern among them is genetically based. The cases consisted of 23 Israeli Jewish patients with histologically confirmed squamous cell carcinoma of the cervix. A group of 162 randomly chosen Israeli Jewish healthy participants, considered to represent the general population, comprised the controls. The germline p53 polymorphism at codon 72 was determined by PCR in DNA obtained from a blood sample taken from each subject. Homozygous arginine was found in 34.8% of cases and in only 14.8% of controls. This difference was statistically significant (P = 0.01). The frequency of homozygous arginine polymorphism in controls was lower than in any other population hitherto reported. It was significantly more common among those of North African than among those of other origin (30.3% vs. 10.8%; P < 0.01). It may be assumed that the low incidence of cervical cancer in Israeli Jewish women and the differences between the ethnic groups may be related to the frequency pattern of the homozygous arginine p53 polymorphism
Asunto(s)
Carcinoma de Células Escamosas/genética , Infecciones por Papillomavirus/genética , Proteína p53 Supresora de Tumor/genética , Infecciones Tumorales por Virus/genética , Neoplasias del Cuello Uterino/genética , Población Blanca/genética , Adulto , Arginina/sangre , Carcinoma de Células Escamosas/sangre , Carcinoma de Células Escamosas/epidemiología , Carcinoma de Células Escamosas/virología , Estudios de Casos y Controles , Codón , Femenino , Predisposición Genética a la Enfermedad , Humanos , Incidencia , Israel/epidemiología , Judíos , Persona de Mediana Edad , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/sangre , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/virología , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Infecciones Tumorales por Virus/sangre , Infecciones Tumorales por Virus/epidemiología , Infecciones Tumorales por Virus/virología , Neoplasias del Cuello Uterino/sangre , Neoplasias del Cuello Uterino/epidemiología , Neoplasias del Cuello Uterino/virologíaRESUMEN
The epidermal growth factor (EGF) receptor is expressed at high levels on many types of tumor cells, such as squamous carcinoma, breast cancer and endothelial cells. We studied targeted delivery of the anticancer drug doxorubicin (DOX) using EGF and its receptor-binding fragment (EGFfr) to cells able to overexpress EGF receptors. EGF-DOX and EGFfr-DOX conjugates were synthesized via a glutaraldehyde bridge. The cytotoxic activities (CTA) of the conjugates were studied in vitro in different tumor cell lines (MCF-7Wt, MCF-7AdrR, B16) and endothelial cells using MTT-test. The antitumor effects of the conjugates were examined in vivo in mice with a subcutaneous B16 model. In the case of MCF-7Wt cells, CTA of EGF-DOX and EGFfr-DOX conjugates exceeded 7.7- and 68-fold that of free DOX. Besides, the conjugates effectively decreased the drug resistance of MCF-7AdrR cells. CTA of the conjugates against endothelial cell cultures markedly exceeded that of free DOX. It is of note that proliferating endothelial cells were much more sensitive to the effects of the conjugates than confluent endothelial cells. Administration of EGF-DOX and EGFfr-DOX conjugates significantly inhibited tumor growth and increased the mean life span of experimental animals by 46 and 48.5%, respectively.
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Antibióticos Antineoplásicos/farmacología , Doxorrubicina/farmacología , Factor de Crecimiento Epidérmico/farmacología , Receptores ErbB/química , Células 3T3 , Animales , Antibióticos Antineoplásicos/química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Doxorrubicina/química , Factor de Crecimiento Epidérmico/química , Factor de Crecimiento Epidérmico/aislamiento & purificación , Receptores ErbB/aislamiento & purificación , Femenino , Fibroblastos , Humanos , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Células Tumorales CultivadasRESUMEN
Outcomes for 11 patients who underwent an in situ tibialis posterior tendon to flexor digitorum longus tendon side-to-side anastamosis as the sole procedure for stage 2 tibialis posterior tendon dysfunction were reviewed. The average follow-up was 34.4 months. Using the American Orthopedic Foot and Ankle Society hindfoot rating scale, a mean improvement of 39.3 points was achieved, with preoperative scores of 38.8 improving to 78.1 postoperatively. Good to excellent results were achieved in nine patients. The in situ side-to-side anastamosis is technically easier to perform, has less tissue trauma, and compares favorably with other soft-tissue procedures and reconstructions for stage 2 tibialis posterior tendon dysfunction. Performing this transfer alone, while leaving the flexor digitorum longus tendon intact, theoretically provides a stronger transfer as the length-tension relationship of the flexor digitorum longus tendon is maintained near its physiologic level. The procedure can consistently restore inversion ability to the rearfoot and stop the progression of tibialis posterior tendon dysfunction.
Asunto(s)
Articulación del Tobillo/cirugía , Procedimientos Ortopédicos/métodos , Transferencia Tendinosa/métodos , Tendones/cirugía , Adulto , Anciano , Anastomosis Quirúrgica/métodos , Articulación del Tobillo/fisiopatología , Femenino , Estudios de Seguimiento , Humanos , Imagen por Resonancia Magnética/métodos , Persona de Mediana Edad , Dolor/diagnóstico , Dolor/fisiopatología , Dimensión del Dolor , Tendinopatía/diagnóstico , Tendinopatía/cirugía , Tibia , Resultado del TratamientoRESUMEN
Cytotoxic activities, accumulation levels and dynamics, and intracellular distribution of the anthracycline antibiotics doxorubicin (DR) and carminomycin (CM) in the free forms or within conjugates with the epidermal growth factor (EGF) were for the first time compared in human breast carcinoma cell lines MCF-7Wt and MCF-7AdrR. The cytotoxic activities of DR and CM conjugates with EGF were higher than the cytotoxic activities of the free antibiotics in both cell lines. The accumulation levels of the free anthracyclines in both cell lines were lower than those of the conjugates and significantly depended on the cell sensitivities to the antibiotics. On receptor-mediated endocytosis of the anthracycline-EGF conjugates, the accumulation levels did not significantly depend on the cell sensitivities to the antibiotics. Both DR and CM, either free or conjugated with EGF, were mainly accumulated in nuclei. The free drugs were accumulated more rapidly, and the accumulation rates of both free and EGF-conjugated CM were higher than those of DR preparations. The intracellular distribution of the free antibiotics significantly depended on the cell sensitivities to the anthracyclines, whereas the cell sensitivities had no effect on the distribution of the conjugates between the nucleus and cytoplasm. The rate of intracellular degradation of DR and CM delivered to target cells within conjugates with EGF was twice lower than that of the free antibiotics. The difference in the accumulation levels and dynamics and in the intracellular distribution of the free and conjugated DR and CM is likely to underlie the higher cytotoxic activities of the anthracycline conjugates with EGF compared to the free drugs.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , Doxorrubicina/farmacología , Factor de Crecimiento Epidérmico/metabolismo , Antibióticos Antineoplásicos/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Doxorrubicina/metabolismo , Doxorrubicina/farmacocinética , Humanos , Células Tumorales CultivadasRESUMEN
Conjugates of carminomycin (Cm) with alpha-fetoprotein (AFP) and epidermal growth factor (EGF) were prepared and their cytotoxic activities were studied in vitro. Both conjugates showed cytotoxic activity which exceeded that of free Cm in tumor cell cultures of MCF-7, SKOV3, QOS, P388 and B16 cells. The antitumor effects of the conjugates were studied in vivo in mice with subcutaneous tumors of B16 and P388 cells. The Cm-AFP and Cm-EGF conjugates inhibited tumor growth and noticeably increased the mean life span in experimental animals. Our results suggest that the therapeutic activity of Cm can be significantly enhanced by conjugation to AFP or EGF.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , Carubicina/farmacología , Factor de Crecimiento Epidérmico/farmacología , alfa-Fetoproteínas/farmacología , Animales , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/química , Carubicina/administración & dosificación , Carubicina/análogos & derivados , División Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Factor de Crecimiento Epidérmico/administración & dosificación , Factor de Crecimiento Epidérmico/análogos & derivados , Humanos , Leucemia P388/tratamiento farmacológico , Leucemia P388/patología , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Trasplante de Neoplasias , Células Tumorales Cultivadas/efectos de los fármacos , alfa-Fetoproteínas/administración & dosificación , alfa-Fetoproteínas/químicaRESUMEN
alpha-Fetoprotein (AFP) was conjugated with doxorubicin (DR) using glutaraldehyde as a cross-linking agent. The protein/DR molar ratio in the conjugate is 1 : 2. Cytotoxic activities (CTA) of the AFP-DR conjugate and of the free DR were compared using human mammary gland carcinoma cells, both DR-sensitive (MCF-7Wt) and DR-resistant (MCF-7AdrR). The CTA of the AFP-DR conjugate was fivefold higher than the CTA of the free DR for sensitive cells of the MCF-7Wt line and sevenfold higher for resistant cells of the MCF-7AdrR line. The CTA of the AFP-DR conjugate was also studied in vitro using the proliferating endothelium taken for a model of endothelial cell lining of blood vessels that supply the tumor. The AFP-DR conjugate was shown to have a high CTA for the endothelial cells (IC50 = 2.5 nM); thus, the conjugate is suggested to manifest an anti-angiogenic effect in vivo. The antitumor activity of the AFP-DR conjugate was studied using mice with inoculated melanoma B16 tumors. The treatment of animals significantly inhibited the tumor growth (>97%) and increased by 60% the mean life span of the animals compared to the control. The high antitumor efficiency of the AFP-DR conjugate and the possibility to significantly decrease the tumor cell resistance to DR make this conjugate a promising chemotherapeutic agent.
Asunto(s)
Antineoplásicos/farmacología , Doxorrubicina/farmacología , alfa-Fetoproteínas/química , Animales , Antineoplásicos/uso terapéutico , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Doxorrubicina/uso terapéutico , Humanos , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/patología , Ratones , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Células Tumorales CultivadasRESUMEN
Covalently bound conjugates of alpha-fetoprotein (AFP) and epidermal growth factor (EGF) with photoheme (PH), 3-desvinyl-3-formylchlorine p6 (Chl p6), chlorine e6 (Chl e6), aluminum disulfochloride phthalocyanine (PC(Al)), and cobalt octa-4,5-carboxyphthalocyanine (teraphthal, TP(Co)) were synthesized. Their molar ratios were 1:4 for AFP-cytotoxin conjugates (cf. 1:10 for AFP-TP(Co)) and 1:2 for EGF conjugates (cf. 1:1 for EGF-PC(Al)). Dark toxicity of both protein conjugates with PH, chlorines, and PC(Al) was much lower than their phototoxicity. Studies on phototoxicity demonstrated that PC(Al) conjugates with AFP and EGF and also EGF-Chl p6 were the most effective. The cytotoxic activity (CTA) of AFP-PC(Al) and EGF-Chl p6 was 80% and of EGF-PC(Al) 64% higher than the CTA of the free drugs. Conjugates with TP(Co) were much more toxic on their activation with ascorbic acid (AA): in the presence of AA the CTA of AFP-TP(Co) and of EGF-TP(Co) was 19 and 61.1% higher, respectively, than the CTA of the free TP(Co).
Asunto(s)
Antineoplásicos/farmacología , División Celular/efectos de los fármacos , Factor de Crecimiento Epidérmico/farmacología , alfa-Fetoproteínas/farmacología , Antineoplásicos/química , Cloro/química , Factor de Crecimiento Epidérmico/química , Hemo/química , Humanos , Indoles/química , Isoindoles , Células Tumorales Cultivadas , alfa-Fetoproteínas/químicaRESUMEN
Epidermal growth factor (EGF) was used as a vector for targeted delivery of phthalocyanines to tumor cells. The conjugates of EGF with disulfochloride aluminum phthalocyanine [Pc(Al)] and disulfochloride cobalt phthalocyanine [Pc(Co)] were synthesized. The cytotoxic activity of the conjugates against the human breast carcinoma cell line MCF-7 was determined. The cytotoxic activity of the EGF-Pc(Co) conjugate was 4.5 times higher than that of the EGF-Pc(Al) conjugate. The antitumor activity of the EGF-Pc(Co) conjugate was also studied in vivo in murine melanoma B16. Compared to free Pc(Co), intravenous injections of Pc(Co) conjugated with EGF inhibited tumor development and increased mean life span and mean survival time of experimental animals.