Diminished functional role and altered localization of SHP2 in non-small cell lung cancer cells with EGFR-activating mutations.

Non-small cell lung cancer (NSCLC) cells harboring activating mutations of the epidermal growth factor receptor (EGFR) tend to display elevated activity of several survival signaling pathways. Surprisingly, these mutations also correlate with reduced phosphorylation of ERK and SHP2, a protein tyrosine phosphatase required for complete ERK activation downstream of most receptor tyrosine kinases. As ERK activity influences cellular response to EGFR inhibition, altered SHP2 function could have a role in the striking response to gefitinib witnessed with EGFR mutation. Here, we demonstrate that impaired SHP2 phosphorylation correlates with diminished SHP2 function in NSCLC cells expressing mutant, versus wild-type, EGFR. In NSCLC cells expressing wild-type EGFR, SHP2 knockdown decreased ERK phosphorylation, basally and in response to gefitinib, and increased cellular sensitivity to gefitinib. In cells expressing EGFR mutants, these effects of SHP2 knockdown were less substantial, but the expression of constitutively active SHP2 reduced cellular sensitivity to gefitinib. In cells expressing EGFR mutants, which do not undergo efficient ligand-mediated endocytosis, SHP2 was basally associated with GRB2-associated binder 1 (GAB1) and EGFR, and SHP2's presence in membrane fractions was dependent on EGFR activity. Whereas EGF promoted a more uniform intracellular distribution of initially centrally localized SHP2 in cells expressing wild-type EGFR, SHP2 was basally evenly distributed and did not redistribute in response to EGF in cells with EGFR mutation. Thus, EGFR mutation may promote association of a fraction of SHP2 at the plasma membrane with adapters that promote SHP2 activity. Consistent with this, SHP2 immunoprecipitated from cells with EGFR mutation was active, and EGF treatment did not change this activity. Overall, our data suggest that a fraction of SHP2 is sequestered at the plasma membrane in cells with EGFR mutation in a way that impedes SHP2's ability to promote ERK activity and identify SHP2 as a potential target for co-inhibition with EGFR in NSCLC.

Condiloma acuminado: eficacia terapéutica comparativa entre el 5-fluorouracilo tópico y la criocirugía / No disponible

ANTECEDENTES. En el condiloma acuminado se han estado utilizando numerosas modalidades terapéuticas; sin embargo, existen pocos estudios que comparen la efectividad entre estas. PACIENTES Y MÉTODO. Se realizó un estudio prospectivo, abierto, para comparar la eficacia terapéutica entre el 5-fluorouracilo en crema al 5% y la criocirugía en el tratamiento tópico del condiloma acuminado. Se incluyeron al azar 40pacientes adultos con este diagnóstico: los primeros 20 pacientes que acudieron a la consulta del consultorio médico de familia 9 del policlínico Managua y los primeros 20 pacientes que acudieron al policlínico docente Joaquín Albarrán, en el período comprendido entre febrero y abril de2006. Se formaron por tanto dos grupos de 20 pacientes cada uno, aplicándose un esquema terapéutico diferente en cada caso, recibiendo los pacientes del policlínico Managua (grupo I) dos aplicaciones semanales de 5-fluorouracilo en crema al 5% y los pacientes del policlínico Joaquín Albarrán (grupo II) una aplicación quincenal de criocirugía. La duración de ambos tratamientos fue la misma (6 semanas en cada grupo).La eficacia terapéutica fue evaluada dos semanas después de culminar el tratamiento, comparando el estado inicial y final de las lesiones. A los pacientes con respuesta total al medicamento se les realizó un seguimiento trimestral durante un año para detectar posibles recidivas. RESULTADO. El análisis pareado inicio-final demostró una respuesta significativa al tratamiento en ambos grupos. Hubo diferencias estadísticamente significativas entre los grupos estudiados. Las tasas de recidivas fueron elevadas en ambos grupos. Los principales eventos adversos observados en ambos grupos fueron: ardor, dolor e inflamación; de intensidad leve y de desaparición espontánea. COMENTARIO. Se demostró que la criocirugía es más eficaz que el 5-fluorouracilo en crema al 5% en el tratamiento tópico del condiloma acuminado (AU)

BACKGROUND. Many different therapies have been used for condyloma acuminata, however, few studies comparing their effectivity have been made. PATIENTS AND METHODS. A prospective, open-label study was conducted to compare therapeutical efficacy between topical 5-fluorouracil (5% cream) and cryosurgery in the topical treatment of condyloma acuminata. Forty adult patients with this diagnosis were randomly chosen, these being the first 20 patients who came to the family doctor’s office 9 in the Managua polyclinic and the first 20 patients who came to the Joaquín Albarrán teaching polyclinic in the period from February to April 2006. Two groups of 20 patients each were formed, applying a different therapeutical scheme in each case. Thus, the patients from the Managua polyclinic (group I) received a twice a week application of topical 5-fluorouracil and those from the Joaquín Albarrán polyclinic (group II) received a fortnightly application of cryosurgery. Both treatments had the same duration (6 weeks in each group). Therapeutical efficacy was assessed two weeks after completing the treatment, comparing the initial and final state of lesions. The patients who responded totally to the medicine were followed-up quarterly for one year in order to detect possible relapses. RESULTS. The start-end comparative analysis showed an outstanding response to the treatment in both groups. There were statistically significant differences between the groups studied. Relapse rates were high in both groups. The majored verse events observed in both group were burning sensation, pain and swelling having mild intensity and spontaneous disappearance. COMMENT. It has been demonstrated that cryosurgery is more effective than topical 5-fluorouracil in the topical treatment of the condyloma acuminate (AU)

Model-based evaluation of nitrogen removal in a tannery wastewater treatment plant.

Computer modelling has been used in the last 15 years as a powerful tool for understanding the behaviour of activated sludge wastewater treatment systems. However, computer models are mainly applied for domestic wastewater treatment plants (WWTPs). Application of these types of models to industrial wastewater treatment plants requires a different model structure and an accurate estimation of the kinetics and stoichiometry of the model parameters, which may be different from the ones used for domestic wastewater. Most of these parameters are strongly dependent on the wastewater composition. In this study a modified version of the activated sludge model No. 1 (ASM 1) was used to describe a tannery WWTP. Several biological tests and complementary physical-chemical analyses were performed to characterise the wastewater and sludge composition in the context of activated sludge modelling. The proposed model was calibrated under steady-state conditions and validated under dynamic flow conditions. The model was successfully used to obtain insight into the existing plant performance, possible extension and options for process optimisation. The model illustrated the potential capacity of the plant to achieve full denitrification and to handle a higher hydraulic load. Moreover, the use of a mathematical model as an effective tool in decision making was demonstrated.

Occupational allergic rhinoconjunctivitis and asthma due to fennel seed.

BACKGROUND: A patient with complaints of rhinitis and asthma occurring at work presented for consultation. OBJECTIVES: To evaluate the role of the foods and spices with which he worked, in the causation of his complaints, and to evaluate his immune reactivity to these materials. METHODS: Allergy skin testing and in vitro RAST assays were carried out. After demonstrating specific reactivity to fennel, SDS-PAGE electrophoreses was carried out. RESULTS: Positive skin tests to grass, ragweed, and freshly prepared fennel seed were found. Serum IgE antibodies to fennel were quite high. Immunoblotting studies showed reactions to two components in fennel extract as well as to components in mugwort, paprika, short ragweed and black pepper. CONCLUSION: This case of occupational rhinitis and asthma in an atopic individual involves sensitivity to unique allergens in fennel, with molecular weights of 67 to 75 KD.

[Variations in the postoperative length of stay according to patient characteristics in a general surgery service]. / Variaciones del tiempo de estancia postoperatoria según las características de los pacientes en un servicio de cirugía general.

With the purpose of identifying factors that explain variations in length of postoperative stay in a general surgery unit, information from 666 clinical records of discharged alive patients was collected. Factors related to the surgical procedure, the severity of the disease and the medical team together with sociodemographic characteristics of the patients were analyzed. Statistical analysis was based on analysis of variance and multiple linear regression. Variables with statistically significant regression coefficients (p < 0.001) were in this order: severity of complications, type of intervention, need for reintervention and severity of diagnosis. Sixty-seven percent of length of stay variation was explained by the included variables. Results allow to suggest an evaluation procedure which takes into account patient and operation characteristics.

Cough-type asthma: a review.

Cough-type asthma is a well-defined entity. The patients typically have a chronic, nonproductive cough that is exacerbated by exercise and upper respiratory tract infections. Bronchial provocation maneuvers are helpful in diagnosing cough-type asthma in older children and adults. Bronchodilators are the mainstay of therapy, although some patients may require cromolyn sodium or inhaled corticosteroids. The natural history of this process suggests that approximately a third to a half of these patients may progress to "classical" asthma with wheezing.