The EPICAL trial, a phase Ib study combining first line afatinib with anti-EGF vaccination in EGFR-mutant metastatic NSCLC.

INTRODUCTION: Combination of anti-EGFR monoclonal antibodies or immune checkpoint inhibitors with TKIs has shown minimal benefit in EGFR mutant (EGFR-mut) NSCLC patients. Consequently, new combination approaches are needed. PATIENTS AND METHODS: The EPICAL was a single arm, phase 1b study to evaluate safety, tolerability and anti-tumor activity of first line afatinib combined with anti-EGF vaccination in advanced EGFR-mut patients. EGFR status and mutations in liquid biopsies were determined by reverse transcriptase-polymerase chain reaction; serum biomarkers by ELISA and Western blotting analysis. RESULTS: The assay enrolled 23 patients, 21 completed the anti-EGF immunization phase. Treatment was well tolerated and no serious adverse events (SAEs) related to the anti-EGF vaccine were reported. Objective response and disease control rates were 78.3% (95%CI = 53.6-92.5) and 95.7% (95%CI = 78.1-99.9), respectively. After a median follow-up of 24.2 months, median progression-free survival (PFS) was 14.8 months (95% CI = 9.5-20.1) and median overall survival (OS) 26.9 months (95% CI = 23.0-30.8). Among the 21 patients completing the immunization phase, PFS was 17.5 months (95% CI = 12.0-23.0) and OS 26.9 months (95% CI = 24.6-NR). At the end of the immunization phase, all 21 patients showed high serum titers of anti-EGF antibodies, while EGF levels had decreased significantly. Finally, treatment with fully immunized patient's sera inhibited the EGFR pathway in tumor cells growing in vitro. CONCLUSIONS: Combination treatment with an anti-EGF vaccine is well tolerated; induces a sustained immunogenic effect and might enhance the clinical efficacy of EGFR TKIs.

Influence of short implants geometry on primary stability.

BACKGROUND: A correct design is needed in short implants to improve primary stability (PS) in low quality bone. This study aimed to compare PS of double thread and single thread short implants. MATERIAL AND METHODS: Thirty implants with single thread design (PHI/SHORT-I) and 30 implants with double thread design (PHIA/SHORT-I) (Radhex®, Inmet-Garnick S.A., Guadalajara, Spain) were placed in 30 randomly selected bovine ribs. PS was assessed in implant stability quotients (ISQ) and periotest values (PV) with Osstell™ and Periotest® devices, respectively. Computed tomographies of the ribs were taken and bone quality was evaluated in Hounsfield Units (HU) using Ez3D Plus software (Vatech Co., Korea). Only implants placed in low quality bone according to Misch and Kircos classification were selected (D3 bone: 350-850 HU; and D4 bone: 150-350 HU). Ten implants were not included in the study for being placed in D1 and D2 bone. Finally, 50 implants were selected: 17 and 9 PHI/SHORT-I in D3 and D4 bone respectively, and 15 and 9 PHIA/SHORT-I in D3 and D4 bone respectively. RESULTS: The one-way ANOVA showed statistically significant differences in ISQ (61.35 ± 4.77 in PHI/SHORT-I and 66.43 ± 4.49 in PHIA/SHORT-I, P<0.005) and PV (-2.76 ± 0.8 and -4.11 ± 1.24 respectively, P<0.005) between two implant designs in D3 bone, and statistically significant differences in ISQ (53.44 ± 3.34 in PHI/SHORT-I and 60.56 ± 1.53 in PHIA/SHORT-I, P<0.0001) and PV (1.13 ± 0.95 and -2.5 ± 0.61 respectively, P<0.0001) between two groups in D4 bone. CONCLUSIONS: Double thread design short implants resulted to have higher PS in comparison with single thread design short implants in D3 and D4 bone.

Implant stability using piezoelectric bone surgery compared with conventional drilling: a systematic review and meta-analysis.

The aim of this systematic review was to assess the primary and secondary stability of dental implants placed at sites prepared with piezoelectric bone surgery (PBS) and conventional drilling (CD). The PubMed/MEDLINE and Cochrane Library databases were searched without date or language restriction up to June 2017. Controlled clinical trials in which each patient received implants placed at sites prepared with both PBS and CD were selected. Implant stability had to be measured on day 0 and during the osseointegration period. Methodological quality was assessed using the Cochrane Collaboration tool. A meta-analysis was performed to compare primary stability (on day 0) and secondary stability (after 2 and 3months) between the two groups. The studies included were determined to have a high risk of bias. There was no significant difference between the two groups for primary stability (on day 0) (P=0.51). After 2 and 3months, secondary stability was statistically higher in implants placed with PBS preparation (P=0.04 and P=0.01, respectively). The implant survival rate was 97.5% in the CD group and 100% in the PBS group. PBS preparation improves secondary stability after 2 and 3months in comparison to CD, with similar implant survival rates. Further studies are needed to determine whether implant osseointegration periods could be shortened with PBS preparation.

Large scale, prospective screening of EGFR mutations in the blood of advanced NSCLC patients to guide treatment decisions.

BACKGROUND: In a significant percentage of advanced non-small-cell lung cancer (NSCLC) patients, tumor tissue is unavailable or insufficient for genetic analyses. We prospectively analyzed if circulating-free DNA (cfDNA) purified from blood can be used as a surrogate in this setting to select patients for treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). PATIENTS AND METHODS: Blood samples were collected in 119 hospitals from 1138 advanced NSCLC patients at presentation (n = 1033) or at progression to EGFR-TKIs (n = 105) with no biopsy or insufficient tumor tissue. Serum and plasma were sent to a central laboratory, cfDNA purified and EGFR mutations analyzed and quantified using a real-time PCR assay. Response data from a subset of patients (n = 18) were retrospectively collected. RESULTS: Of 1033 NSCLC patients at presentation, 1026 were assessable; with a prevalence of males and former or current smokers. Sensitizing mutations were found in the cfDNA of 113 patients (11%); with a majority of females, never smokers and exon 19 deletions. Thirty-one patients were positive only in plasma and 11 in serum alone and mutation load was higher in plasma and in cases with exon 19 deletions. More than 50% of samples had <10 pg mutated genomes/µl with allelic fractions below 0.25%. Patients treated first line with TKIs based exclusively on EGFR positivity in blood had an ORR of 72% and a median PFS of 11 months. Of 105 patients screened after progression to EGFR-TKIs, sensitizing mutations were found in 56.2% and the p.T790M resistance mutation in 35.2%. CONCLUSIONS: Large-scale EGFR testing in the blood of unselected advanced NSCLC patients is feasible and can be used to select patients for targeted therapy when testing cannot be done in tissue. The characteristics and clinical outcomes to TKI treatment of the EGFR-mutated patients identified are undistinguishable from those positive in tumor.

La hibridación in situ fluorescente en la predicción de recurrencia del carcinoma urotelial / Fluorescent in situ Hybridization as a Predictor of Relapse in Urotelial Carcinoma

Objetivo: Evaluar la utilidad del estudio de alteraciones cromosómicas mediante hibridación in situ fluorescente en una serie de pacientes diagnosticados de carcinoma urotelial con un seguimiento mínimo de 24 meses, y analizar su posible efecto anticipador. Material y métodos: La serie global incluye 338 muestras procedentes de 98 pacientes con 84 episodios de carcinoma urotelial. Para evaluar la capacidad de predicción del test se estudió un subgrupo de 24 pacientes que presentaron como mínimo una recurrencia a lo largo del seguimiento (serie de recurrencia). Se consideraron 3 categorías (episodio coherente positivo, episodio coherente negativo y episodio no coherente) en función de la relación entre los resultados de la hibridación in situ fluorescente del estudio concomitante al nuevo episodio y las muestras precedentes. Resultados: La hibridación in situ fluorescente presentó mayor sensibilidad independientemente del grado, valor predictivo negativo y exactitud, mientras que la especificidad y el valor predictivo positivo fueron superiores para la citología convencional. En la serie de recurrencia 19/29 episodios resultaron coherentes, 11/19 fueron coherentes positivos, todos con carcinoma urotelial de alto grado, y 8/19 coherentes negativos, la mayoría de bajo grado. Conclusiones: La hibridación in situ fluorescente muestra una alta sensibilidad en un seguimiento de 24 meses, y es capaz de predecir recurrencias, especialmente en casos de alto grado. Nuestros datos demuestran también la existencia de carcinomas uroteliales sin alteraciones cromosómicas detectables con la metodología actualmente disponible. Los resultados apoyan un seguimiento multidisciplinar con la utilización combinada de la hibridación in situ fluorescente, citología y cistoscopia (AU)

Objective: To assess the value of the study of chromosomal alterations by fluorescent in situ hybridization in a series of patients diagnosed of urothelial carcinoma and a minimum follow up of twenty four months, as well as evaluate its putative predictive potential. Material and methods: The overall series includes 338 samples from 98 patients with 84 episodes of urothelial carcinoma. A subgroup of 24 patients who had at least one recurrence during the follow up was used to evaluate the predictive potential of the test. Three categories were considered (positive coherent episode, negative coherent episode, and incoherent episode) depending on the relationship between the fluorescent in situ hybridization result in the concomitant study of the new episode and those of the preceding samples. Results: Fluorescent in situ hybridization showed higher sensitivity regardless of grade, negative predictive value and accuracy, while specificity and positive predictive value were superior with conventional cytology. In the recurrence, series 19/29 episodes were coherent, 11/19 were positive coherent with urothelial carcinoma all high grade and 8/19 negative coherent, most low grade. Conclusions: Fluorescent in situ hybridization test shows good sensitivity during a follow up of twenty four months and is able to predict recurrence, especially in cases of high grade. Our data demonstrate the existence of urothelial carcinomas without detectable chromosomal abnormalities by currently available methodology. The results support a multidisciplinary follow up combining fluorescent in situ hybridization, cytology and cystoscopy (AU)

Fluorescent in situ hybridization as a predictor of relapse in urothelial carcinoma.

OBJECTIVE: To assess the value of the study of chromosomal alterations by fluorescent in situ hybridization in a series of patients diagnosed of urothelial carcinoma and a minimum follow up of twenty four months, as well as evaluate its putative predictive potential. MATERIAL AND METHODS: The overall series includes 338 samples from 98 patients with 84 episodes of urothelial carcinoma. A subgroup of 24 patients who had at least one recurrence during the follow up was used to evaluate the predictive potential of the test. Three categories were considered (positive coherent episode, negative coherent episode, and incoherent episode) depending on the relationship between the fluorescent in situ hybridization result in the concomitant study of the new episode and those of the preceding samples. RESULTS: Fluorescent in situ hybridization showed higher sensitivity regardless of grade, negative predictive value and accuracy, while specificity and positive predictive value were superior with conventional cytology. In the recurrence, series 19/29 episodes were coherent, 11/19 were positive coherent with urothelial carcinoma all high grade and 8/19 negative coherent, most low grade. CONCLUSIONS: Fluorescent in situ hybridization test shows good sensitivity during a follow up of twenty four months and is able to predict recurrence, especially in cases of high grade. Our data demonstrate the existence of urothelial carcinomas without detectable chromosomal abnormalities by currently available methodology. The results support a multidisciplinary follow up combining fluorescent in situ hybridization, cytology and cystoscopy.

Análisis de las ventajas de la diálisis peritoneal en el tratamiento de la insuficiencia cardíaca refractaria crónica / No disponible

No disponible

The administration of oleoyl-estrone to lactating dams induces selective changes in the normal growth pattern of their pups.

To determine the effects of oleoyl-estrone treatment on the lactating dams and on the growth pattern of developing rats, female Wistar rats were randomly divided into two groups after delivery. One group received a daily gavage of 0.2 mL sunflower oil containing 10 micromol oleoyl-estrone/kg (treated group) and the other received a daily intragastric gavage of 0.2 mL sunflower oil (control group). Treatment was carried out during the first 15 days of lactation. Dams were killed on days 1, 15 or 20 after delivery and pups were sacrificed on days 1, 15, 20 or 30. Treated dams showed a transient decrease in food intake, significant lower lipid content than control dams, with a parallel maintenance of protein content and no appreciative changes in plasmatic parameters. However, a significant increase in brown adipose tissue mass was detected in treated group. Pups from treated dams showed a decrease in their growth rate that was reflected in the lower adipose tissue mass in different locations, except in the case of brown adipose tissue and, that continued after cessation of treatment. Thus, treatment affects dams in a selective way that does not coincide with a simple food restriction model.

Different uptake and handling of oleoyl-estrone by fetuses and neonatal rats.

To determine whether oleoyl-estrone can be transferred from mothers to their offspring either during pregnancy or lactation, a gavage of tracer dose of (3)H-Oleoyl-estrone was given to 21-day pregnant rats and to lactating rats on day 15 after delivery. In pregnant rats, the label was found in maternal blood as well as in liver and fetal serum, the latter showing the highest specific activity observed. In lactating rats, oleoyl-estrone label was found both in the mammary gland and maternal serum; in the pups, label was found in their stomach contents (i.e., clotted milk) and serum. The results suggest that the placenta effectively blocks the passage of oleoyl-estrone to the fetuses probably because of its high esterase activity. On the other hand, oleoyl-estrone is easily transferred from dams to pups, as a component of milk.

Involvement of IFNbeta on IFNgamma and nitric oxide (NO) production by bone marrow (BM) cells in response to lipopolysaccharide.

Bone marrow (BM) cells fractioned in Percoll gradients yield a low-density fraction (Fr3) highly enriched in suppressor activity. Previously, it has been demonstrated that BM associated suppressor activity was mediated by early myeloid cells, through a mechanism dependent on endogenous IFNgamma and nitric oxide production after bacterial stimuli, e.g. lipopolysaccharide (LPS). However, the mechanism(s) through which the IFNgamma is produced in BM has not yet been fully elucidated. Therefore, in the present study we investigated the involvement of IL-12, IL-18 and IFNbeta on the production of IFNgamma and nitric oxide in cultures of BM Fr3 cells, and characterized the IFNgamma-producing cells, in response to LPS. The results show that both IL-12 and IFNbeta, but not IL-18, are involved on IFNgamma production. However, only IFNbeta appears to be critical on nitric oxide production. Furthermore, we found that cells of the Thy1.2+CD3+ phenotype produce IFNgamma and are tightly involved on nitric oxide production by BM Fr3 cells. In conclusion, IFNbeta appears to be critical on IFNgamma- and nitric oxide production by BM cells in response to LPS, through a mechanism that is dependent on Thy1.2+CD3+ IFNgamma-producing cells.

Weight loss with long-term intermittent treatment with oral oleoyl-estrone in lean Zucker male rats.

To determine whether or not the long-term intermittent treatment with oleoyl-estrone (OE) in rats induces a cumulative weight loss, adult male rats were treated with OE over three alternating 10-day periods, with a 30-day "recovery" period occurring between each period. At the end of the third treatment period, the rats were allowed to recover and were then mated with females. Each treatment period produced a decrease of ca. 7% in body weight with no rebound during the recovery periods, whereas weight changed at the same pace in controls. The greatest difference in body weight was observed during the last days of treatment. OE-treated rats retained their initial protein pools throughout the treatment. Furthermore, treated and control males remained fertile and were able to procreate. Thus, we can conclude that intermittent OE treatment induces a cumulative weight loss in adult male rats.

[Assessment of cardiovascular risk in population groups. Comparison of Score system and Framingham in hypertensive patients]. / Valoración de riesgo cardiovascular en grupos de población. Comparación de los sistemas Score y Framingham en pacientes hipertensos.

INTRODUCTION AND OBJECTIVES: Calculation of cardiovascular risk in populations allows for developing and assessing of intervention programs and adapting health resources. While the Framingham System has been used in the past, a group of European researchers have proposed a different method called the Score project. The purpose of this paper is to compare the value of both methods for assessing cardiovascular risk. METHODS: In 6,775 evaluable hypertensive patients distributed over the 17 Spanish autonomous communities (ACs), the 10-year risk of experiencing a coronary event (CR) was calculated using the Framingham equation, while risk of coronary death (RCD) and vascular death (RVD) was calculated using the Score project system, both at baseline and after one year of blood pressure control with amlodipine at the required dose. A comparison was made of the capacity to detect risk differences by both methods between populations with known different risks, and in the same population as a result of blood pressure control. RESULTS: Both the Score and the Framingham systems detected the significant decrease in both CR and RCD or RVD at one year of application of the CORONARIA study protocol. Risk decrease measured by any of the two methods was significant (p < 0.05) overall, by genders, and by ACs. However, the Score System, unlike the Framingham system, could not detect the reported differences in the mortality risk for coronary and vascular disease between the ACs of the North and the South-East parts of Spain.

Valoración de riesgo cardiovascular en grupos de población. Comparación de los sistemas Score y Framingham en pacientes hipertensos / Assessment of cardiovascular risk in population groups. Comparison of Score system and Framingham in hypertensive patients

Introducción y objetivos. El cálculo del riesgo cardiovascular en poblaciones permite desarrollar programas de intervención y adecuar recursos sanitarios. En el pasado se ha utilizado el sistema de Framingham, actualmente un grupo europeo ha propuesto el método Score. Nos proponemos comparar la utilidad de ambos métodos en la valoración del riesgo cardiovascular. Métodos. En 6.775 pacientes hipertensos valorables, procedentes de las 17 Comunidades Autónomas (CC.AA.) de España, se calculó el riesgo de padecer un accidente coronario (RC) en los siguientes 10 años (Framingham) y el riesgo de muerte por enfermedad coronaria (RMC) y por enfermedad vascular (RMV) (Score), tanto en situación basal como tras un año de control de la presión arterial mediante amlodipino. Se comparó la capacidad para detectar diferencias de riesgo entre distintas poblaciones con morbimortalidad cardiovascular diferente y en la misma población como consecuencia del control de la presión arterial. Resultados. Tanto el sistema Score como el de Framingham detectaron el descenso del riesgo de accidente coronario y del de muerte por causa coronaria o vascular, secundario al control de la presión arterial. El descenso del riesgo en cualquiera de los dos métodos fue significativo (p < 0,05) en datos globales, por sexos y por CC.AA. Sin embargo el sistema Score, al contrario que el de Framingham, no fue capaz de detectar las diferencias RMC y RMV, que han sido descritas entre las CC.AA. del norte de España y las del Sureste

Introduction and objectives. Calculation of cardiovascular risk in populations allows for developing and assessing of intervention programs and adapting health resources. While the Framingham System has been used in the past, a group of European researchers have proposed a different method called the Score project. The purpose of this paper is to compare the value of both methods for assessing cardiovascular risk. Methods. In 6,775 evaluable hypertensive patients distributed over the 17 Spanish autonomous communities (ACs), the 10-year risk of experiencing a coronary event (CR) was calculated using the Framingham equation, while risk of coronary death (RCD) and vascular death (RVD) was calculated using the Score project system, both at baseline and after one year of blood pressure control with amlodipine at the required dose. A comparison was made of the capacity to detect risk differences by both methods between populations with known different risks, and in the same population as a result of blood pressure control. Results. Both the Score and the Framingham systems detected the significant decrease in both CR and RCD or RVD at one year of application of the CORONARIA study protocol. Risk decrease measured by any of the two methods was significant (p < 0.05) overall, by genders, and by ACs. However, the Score System, unlike the Framingham system, could not detect the reported differences in the mortality risk for coronary and vascular disease between the ACs of the North and the South-East parts of Spain

Technical note: Measurement of total estrone content in foods. Application to dairy products.

Estrone is a powerful growth-inducing hormone that is present in milk, mainly in the form of fatty acid esters, at concentrations that promote growth in experimental animals. We present here a method useful for the measurement of this natural hormone in foods and applied it to several common dairy products. Samples were frozen, finely powdered, and lyophilized then extracted with trichloromethane/methanol; the dry extract was saponified with potassium hydroxide. The free estrone evolved was extracted with ethyl acetate and was used for the estimation of total estrone content through radioimmunoassay. Application of the method to dairy products showed high relative levels of total estrone (essentially acyl-estrone) in milk, in the range of 1 microM, which were halved in skimmed milk. Free estrone levels were much lower, in the nanomolar range. A large proportion of estrone esters was present in all other dairy products, fairly correlated with their fat content. The amount of estrone carried by milk is well within the range, where its intake may exert a physiological response in the sucklings for which it is provided. These growth-inducing and energy expenditure-lowering effects may affect humans ingesting significant amounts of dairy products.

[Coronary risk differences in hypertensive patients of different autonomous communities. CORONARY study]. / Diferencias de riesgo coronario en pacientes hipertensos de las Comunidades Autónomas. Estudio CORONARIA.

OBJECTIVES: Various articles describe the existence of differences in cardiovascular morbidity and mortality between different Spanish Autonomous Communities (SACs). We have intended to know if there are coherent differences in hypertensive patients cardiovascular risk. MATERIAL AND METHODS: 1,720 family physicians distributed in the 17 SACs as the number of inhabitants of each one selected 5 consecutive patients maximum within a period of 2 months, with blood pressure > or = 140/90 mmHg and at least another coronary risk factor. In 6,775 of 7,469 patients (51% males), the risk of a coronary event (CE) in the next 10 years according to Framingham equation and the risk of fatal cardiovascular event (RCV) according to Score formula were calculated. RESULTS: CE calculated in the group of patients in primary prevention (and without diabetes) in northern SACs (Cantábrico) was 18.8%, and 20.5% in south-east SACs (Mediterranean) (p < 0.0001). In addition, CE in secondary prevention was 26.1% in northern SACs and 28.6% in south-east SACs (p < 0.0001). The differences remained upon considering diabetics in primary prevention. There were no significant differences, however, in the risk of cardiovascular death (Score) between both areas, being 8.9% in the north and 8.8% in the south-east. CONCLUSIONS: Our study demonstrates that coronary risk is increased in hypertensive populations of south east SACs with respect to SACs of the north and to national average, while the risk of suffering a fatal cardiovascular event is not different.

Estatinas en el tratamiento de la hipertensión arterial / Statins in the treatment of arterial hypertension

La enfermedad cardiovascular y cerebrovascular continúa siendo una de las causas principales de mortalidad en los países occidentales. La modificación de todos y cada uno de los factores de riesgo de una forma integrada resulta esencial para conseguir una reducción óptima de los episodios cardiovasculares. De hecho, el beneficio del tratamiento antihipertensivo quedaba significativamente limitado cuando no se modificaban o empeoraban los niveles de colesterol. En la población general se sabe que existe una asociación entre la presencia de niveles elevados de colesterol y de la presión arterial (PA), tanto en pacientes hipertensos como en la hipertensión (HTA) límite, y también se ha observado que la prevalencia de hipercolesterolemia por encima de 240 mg/dl es el doble en hipertensos que en normotensos y que existe además una agregación familiar entre la HTA, hiperlipidemia y la resistencia a la insulina. La importancia de estas asociaciones de factores de riesgo radica en que la elevación tanto de cifras de PA como de niveles de colesterol provoca no una suma del riesgo del accidente cardiovascular, sino que se observa un incremento casi exponencial de este riesgo. Pese a la frecuente asociación entre HTA e hiperlipidemia se conoce relativamente poco sobre posibles mecanismos patogénicos comunes o sobre el efecto que la terapia provoca en ambos y en la protección de los órganos diana. Todos los datos orientan a que debe existir algún mecanismo que directa o indirectamente sea responsable tanto de la elevación de los niveles de colesterol como de la elevación de la PA (AU)

La producción de óxido nítrico por células supresoras mieloides puede ser resistente o sensible a la acción de los glucocorticoides dependiendo del tipo de co-estimulación. El efecto de la señalización a través de endotoxina frente al TNF-alfa / Sensitivity of nitric oxide production by myeloid suppressor cells to glucocorticoids depends on the type of stimulation

Las células supresoras mieloides producen una gran cantidad de óxido nítrico (NO) cuando son activadas con IFN más otras señales co-estimuladoras. Hemos estudiado el efecto inhibidor de los glucocorticoides (GC) sobre esta producción cuando las células se co-estimulan con endotoxina (LPS) o TNF. Los resultados muestran que el NO inducido por IFN en presencia de LPS (rango 0,1 - 10 µg/mL) es altamente resistente a la acción inhibidora de los GC (10- 6, 10- 7 M). En estos cultivos el TNF endógeno no es requerido para esa producción, como se evidencia en ensayos de neutralización. Por el contrario, el NO que se induce con IFN en presencia de cantidades mínimas de LPS (1 ng/mL) es muy sensible a la acción inhibidora de los GC. En estos cultivos, el TNF endógeno es necesario para esa inducción. En ausencia de LPS la producción de NO también es sensible a los GC cuando las señales co-estimuladoras dependen de TNF (TNF, TNF-RI, o CD40). Estos resultados indican que la producción NO por las células supresoras mieloides activadas con IFN muestran una sensibilidad muy diferente a los GC que depende del tipo de señales de co-estimulación presentes. Mientras que esta producción es resistente a los GC cuando las células son co-estimuladas con endotoxina por una vía independiente de TNF, la producción de NO es muy sensible a los GC si la co-estimulación depende de esta vía. (AU)